Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study
TL;DR: Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal S GLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.
Abstract: OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption . RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3 H-glucose, 14 C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (R a O) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC 0–2h ] reductions of 35% and 43%, respectively; P 0–6h , 18.2 ± 5.6 vs. P a O. Canagliflozin reduced AUC R a O by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P P = 0.002). Over 2 to 6 h, canagliflozin increased R a O such that total AUC R a O over 0 to 6 h was P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in R a O. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying R a O, likely due to intestinal SGLT1 inhibition.
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TL;DR: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas is presented.
Abstract: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024
1,740 citations
TL;DR: In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia.
Abstract: Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes.
Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m2, HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.
Results. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol•min–1•m–2•mM–1 and 55 [IQR, 39] pmol•min–1•m–2•mM–1 vs. 44 [IQR, 32] pmol•min–1•m–2•mM–1, P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged.
Conclusions. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid.
Trial registration. ClinicalTrials.Gov {"type":"clinical-trial","attrs":{"text":"NCT01248364","term_id":"NCT01248364"}}NCT01248364 (EudraCT no. 2010-018708-99).
Funding. This study was funded by Boehringer Ingelheim.
862 citations
TL;DR: Some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease.
Abstract: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
859 citations
TL;DR: The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise.
Abstract: Aims
Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise.
Methods
In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study.
Results
At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (−0.77, −1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups.
Conclusion
Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.
552 citations
TL;DR: In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease.
Abstract: Inhibitors of sodium–glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug–drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12–104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.
405 citations
Cites background from "Canagliflozin Lowers Postprandial G..."
...After multiple doses of dapagliflozin, UGE was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM [13]....
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...Canagliflozin dose-dependently reduced the calculated renal threshold for glucose excretion and increased UGE in healthy subjects [64]....
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...In a short-term 12-week trial evaluating five doses of canagliflozin (50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily), when compared with control subjects (placebo or sitagliptin 100 mg/day), canagliflozin increased UGE but was not associated with increased bacteriuria or adverse event reports of UTIs [88]....
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...They specifically target the kidney by blocking the reabsorption of filtered glucose, thus leading to increased urinary glucose excretion (UGE), especially when hyperglycaemia is present [5, 6]....
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...Besides increasing UGE, dapagliflozin exerts indirect metabolic effects [27]....
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References
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TL;DR: Apres l'ingestion de glucose, l'insulino-secretion du pancreas est stimulee et la combinaison de l'hyperglycemie et de l-hyperinsulinemie doit induire la captation de glucose dans les territoires splanchique et peripherique (muscles) and the suppression of the production hepatique du glucose.
Abstract: Apres l'ingestion de glucose, l'insulino-secretion du pancreas est stimulee et la combinaison de l'hyperglycemie et de l'hyperinsulinemie doit induire la captation de glucose dans les territoires splanchique (foie et tube digestif) et peripherique (muscles) et la suppression de la production hepatique du glucose. Le but de cette conference est de prouver que, bien que la perturbation du metabolisme hepatique du glucose joue un role dans le maintien de l'etat diabetique, le foie ne joue probablement pas de role majeur dans le developpement precoce de l'hyperglycemie a jeun des DNID
2,394 citations
TL;DR: A personal review of advances in the genetics, molecular biology, biochemistry, biophysics, and structure of SGLTs, including cotransporters for sugars, anions, vitamins, and short-chain fatty acids.
Abstract: There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The ...
1,082 citations
"Canagliflozin Lowers Postprandial G..." refers result in this paper
...This is in contrast to serious malabsorption symptoms observed in individuals with inactivating genetic mutations in SGLT1 (3)....
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01 Jan 2005
TL;DR: Assessment of the impact on clinical practice of broadening indications for statins in stroke beyond current US and European guidelines finds guidelines for definite initiation of statin treatment were met by 48% of patients for the National Cholesterol EducationProgramAdultTreatmentPanelIII, 38% for the European Joint Task Force II, and 100% forThe Food and Drug Administration.
Abstract: Background:NewUSFoodandDrugAdministrationlabeling in 2003 recognizes stroke and evidence of cerebrovasculardiseaseasindicatorconditionsforinitiatingstatin (simvastatin) therapy, based on results of the Heart Protection Study, thereby extending the indications for statins in stroke beyond current US and European guidelines. Objective: To assess the impact on clinical practice of broadeningindicationsforstatinsinpatientswithstroke. Design: Observational study. Setting: University hospital stroke service. Patients: One hundred consecutive patients with ischemic stroke and transient ischemic attack. Interventions: Development and application of algorithmsforinitiatingstatintherapyinpatientswithstroke and transient ischemia abstracted from recent national and international guidelines (National Cholesterol EducationProgramAdultTreatmentPanelIII,EuropeanJoint TaskForceII),HeartProtectionStudyentrycriteria,and Heart Protection Study–based US Food and Drug Administration labeling. Main Outcome Measures:Percentages of patients who met clinical trial–validated and US Food and Drug Administration–approved criteria for initiation of statin therapy. Results: Patient age averaged 74 years (range, 35-96 years);64%werefemale,and74%werewhite.Strokesubtype was large-vessel atherosclerosis in 24%, cardioembolic in 44%, small-vessel atherosclerosis in 22%, and other in 10%. Twenty of 100 patients were already taking statins on admission. Guidelines for definite initiation of statin treatment were met by 48% of patients for theNationalCholesterolEducationProgramIII,38%for the European Joint Task Force II, 92% for the Heart Protection Study, and 100% for the Food and Drug Administration.
834 citations
TL;DR: In this paper, the factors responsible for fasting hyperglycemia were investigated in 77 normal weight non-insulin-dependent diabetic and 72 age-, sex-, and weight-matched control individuals.
Abstract: The factors responsible for fasting hyperglycemia were investigated in 77 normal weight non-insulin-dependent diabetic (NIDD) and 72 age-, sex-, and weight-matched control individuals. In diabetic subjects with mild fasting hyperglycemia (less than 140 mg/dL) hepatic glucose production (1.85 +/- 0.03 mg/kg.min) was similar to controls (1.84 +/- 0.02); the major factor responsible for the elevated basal glucose level in the diabetic group was a decreased efficiency in the tissue uptake of glucose, as reflected by a 30% decline in the rate of glucose clearance (1.56 +/- 0.03 v 2.00 +/- 0.03 mL/kg.min, P less than .001). In contrast, in diabetic subjects with fasting plasma glucose concentrations above 140 mg/dL, basal hepatic glucose production was significantly elevated (2.42 +/- 0.08 mg/kg.min, P less than .001) and correlated closely with the increase in fasting plasma glucose concentration (r = .796, P less than .001). The basal rate of whole body glucose clearance reached a plateau value at fasting glucose levels of 160 to 180 mg/dL and did not contribute to the further rise in fasting plasma glucose concentrations above 160 to 180 mg/dL. Decreased efficiency of tissue glucose uptake is responsible the development of fasting hyperglycemia in patients with mild NIDDM (fasting plasma glucose less than 140 mg/dL). As the diabetic state worsens, an increase in basal hepatic glucose production is the major factor responsible for the progressive rise in fasting glucose levels.
530 citations
TL;DR: In this article, the role of SGLT1 in small intestine and kidney glucose absorption was investigated in Sglt1(-/-) mice, which developed a glucose-galactose malabsorption syndrome.
Abstract: To clarify the physiological role of Na(+)-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1(-/-) mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1(-/-) mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ∼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2.
519 citations