Dapagliflozin

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Anna Maria Langkilde - One of the best experts on this subject based on the ideXlab platform.

  • albuminuria lowering effect of Dapagliflozin alone and in combination with saxagliptin and effect of Dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease delight a randomised double blind placebo controlled trial
    The Lancet Diabetes & Endocrinology, 2019
    Co-Authors: Carol A Pollock, Bergur V Stefansson, David C Sjostrom, Anna Maria Langkilde, Daniel Reyner, Peter Rossing, David C Wheeler, Hiddo J L Heerspink
    Abstract:

    Summary Background In patients with type 2 diabetes, intensive glucose control can be renoprotective and albuminuria-lowering treatments can slow the deterioration of kidney function. We assessed the albuminuria-lowering effect of the sodium-glucose co-transporter-2 inhibitor Dapagliflozin with and without the dipeptidyl peptidase-4 inhibitor saxagliptin, and the effect of Dapagliflozin–saxagliptin on glycaemic control in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. Methods In this double-blind, placebo-controlled trial (DELIGHT), we enrolled patients at 116 research centres in Australia, Canada, Japan, South Korea, Mexico, South Africa, Spain, Taiwan, and the USA. We included patients with a known history of type 2 diabetes, increased albuminuria (urine albumin-to-creatinine ratio [UACR] 30–3500 mg/g), an estimated glomerular filtration rate of 25–75 mL/min per 1·73 m2, and an HbA1c of 7·0–11·0% (53–97 mmol/mol), who had been receiving stable doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and glucose-lowering treatment for at least 12 weeks. After a 4-week, single-blind placebo run-in period, participants were randomly assigned (1:1:1; via an interactive voice–web response system) to receive Dapagliflozin (10 mg) only, Dapagliflozin (10 mg) and saxagliptin (2·5 mg), or placebo once-daily for 24 weeks. Primary endpoints were change from baseline in UACR (Dapagliflozin and Dapagliflozin–saxagliptin groups) and HbA1c (Dapagliflozin–saxagliptin group) at week 24 in all randomly allocated patients with available data (full analysis set). This study is registered with ClinicalTrials.gov, number NCT02547935 and is completed. Findings The study took place between July 14, 2015, and May 18, 2018. 1187 patients were screened, of whom 461 were randomly assigned: 145 to the Dapagliflozin group, 155 to the Dapagliflozin–saxagliptin group, and 148 to the placebo group (13 patients were excluded because of data integrity issues). Dapagliflozin and Dapagliflozin–saxagliptin reduced UACR versus placebo throughout the study period. At week 24, the difference (vs placebo; n=134 patients with available data) in mean UACR change from baseline was −21·0% (95% CI −34·1 to −5·2; p=0·011) for Dapagliflozin (n=132) and −38·0% (−48·2 to −25·8; p Interpretation Dapagliflozin with or without saxagliptin, given in addition to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, is a potentially attractive option to slow the progression of kidney disease in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. Funding AstraZeneca.

  • efficacy and safety of Dapagliflozin in patients with type 2 diabetes and moderate renal impairment chronic kidney disease stage 3a the derive study
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Paola Fioretto, David C Sjostrom, Ronald Goldenberg, Peter Sartipy, Anna Maria Langkilde, Stefano Del Prato, John B Buse, Francesco Giorgino, Daniel Reyner
    Abstract:

    AIMS Dapagliflozin is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2). This study assessed the efficacy and safety of Dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45-59 mL/min/1.73 m2 ; chronic kidney disease [CKD] stage 3A). MATERIALS AND METHODS In this double-blind, parallel group, Phase 3 study (NCT02413398, clinicaltrials.gov) patients with inadequately controlled T2D (HbA1c 7.0%-11.0%) were randomized (1:1) to Dapagliflozin 10 mg once daily (N = 160) or matching placebo (N = 161) for 24 weeks. Randomization was stratified by pre-enrolment glucose-lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24. RESULTS At Week 24, compared with placebo, Dapagliflozin significantly decreased HbA1c (difference [95% CI], -0.34% [-0.53, -0.15]; P < 0.001), body weight (difference [95% CI], -1.25 kg [-1.90, -0.59]; P < 0.001), fasting plasma glucose (difference [95% CI], -0.9 mmol/L [-1.5, -0.4]; P = 0.001) and systolic blood pressure (difference [95% CI], -3.1 mm Hg [-6.3, 0.0]; P < 0.05). Decreases from baseline in eGFR were greater with Dapagliflozin than placebo at Week 24 (-2.49 mL/min/1.73 m2 [-4.96, -0.02]), however, eGFR returned to baseline levels at Week 27 (3 weeks post-treatment) (0.61 mL/min/1.73 m2 [-1.59, 2.81]). No increase in adverse events (AEs; 41.9% vs 47.8%) or serious AEs (5.6% vs 8.7%) were reported with Dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported. CONCLUSIONS The findings of this study (NCT02413398, clinicaltrials.gov) support the positive benefit/risk profile of Dapagliflozin for the treatment of patients with T2D and CKD 3A.

  • Dapagliflozin in patients with type 2 diabetes mellitus a pooled analysis of safety data from phase iib iii clinical trials
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Serge Jabbour, Jochen Seufert, Andre Scheen, Clifford J Bailey, Cathrina Karup, Anna Maria Langkilde
    Abstract:

    Aim: To evaluate the safety and tolerability of Dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM). Methods: Data were pooled from 13 placebo-controlled trials of up to 24weeks' duration (Dapagliflozin, n=2360; placebo, n=2295). Larger placebo-/comparator-controlled pools of 21 (≤208weeks; Dapagliflozin, n=5936; control, n=3403) and 30 trials (≥12weeks; Dapagliflozin, n=9195; control, n=4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively. Results: Over 24weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for Dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with Dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with Dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving Dapagliflozin and control, respectively. Conclusion: The overall incidence rates of AEs and SAEs were similar in the Dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with Dapagliflozin than placebo.

  • efficacy and safety of Dapagliflozin in patients with inadequately controlled type 1 diabetes depict 1 24 week results from a multicentre double blind phase 3 randomised controlled trial
    The Lancet Diabetes & Endocrinology, 2017
    Co-Authors: P Dandona, Anna Maria Langkilde, Steven C Griffen, Lars Hansen, Chantal Mathieu, Fredrik Thoren, Moshe Phillip, D Tschope, Joseph Proietto, Stephen N Stranks
    Abstract:

    Summary Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of Dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA 1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to Dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA 1c . The primary efficacy outcome was the change from baseline in HbA 1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only Dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (Dapagliflozin 5 mg [n=277] vs Dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA 1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of Dapagliflozin significantly reduced HbA 1c compared with placebo (mean difference from baseline to week 24 for Dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p vs placebo was −0·45% [−0·58 to −0·31; p vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the Dapagliflozin 5 mg, Dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the Dapagliflozin 5 mg group, five (2%) in the Dapagliflozin 10 mg group, and three (1%) in the placebo group. Interpretation Our results suggest that Dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. Funding AstraZeneca and Bristol-Myers Squibb.

  • durability of glycaemic efficacy over 2 years with Dapagliflozin versus glipizide as add on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin
    Diabetes Obesity and Metabolism, 2014
    Co-Authors: Michael A Nauck, Santiago Durangarcia, K Rohwedder, S Del Prato, Anna Maria Langkilde, Jennifer Sugg, S J Parikh
    Abstract:

    Aims To assess the long-term glycaemic durability, safety and tolerability of Dapagliflozin versus glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled by metformin alone. Methods This was a 52-week, randomised, double-blind study of Dapagliflozin (n = 406) versus glipizide (n = 408), uptitrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 and 20 mg/day, respectively, as add-on therapies to metformin (≥1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. Results In total, 53.1% of patients completed 104 weeks of treatment. After the greater initial decrease (0–18 weeks) in glycated haemoglobin (HbA1c) with glipizide, the 18–104-week HbA1c coefficient of failure (CoF) was lower with Dapagliflozin (0.13%/year) than with glipizide (0.59%/year), resulting in significant Dapagliflozin versus glipizide differences of −0.46%/year (95% CI −0.60,−0.33; p = 0.0001) for CoF and −0.18%(−2.0 mmol/mol) [95% CI −0.33(−3.6),−0.03(−0.3); p = 0.021] for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure, whereas glipizide increased weight and systolic blood pressure, giving 104-week Dapagliflozin versus glipizide differences of −5.1 kg (95% CI: −5.7,−4.4) and −3.9 mmHg (95% CI: −6.1,−1.7), respectively. Over 104 weeks, the hypoglycaemia rate was 10-fold lower with Dapagliflozin than with glipizide (4.2 vs. 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection (UTI) were greater with Dapagliflozin (14.8 and 13.5%, respectively) than with glipizide (2.9 and 9.1%, respectively). Conclusions Over 2 years, compared with glipizide, Dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and systolic blood pressure and a low hypoglycaemia rate; however, genital infections and UTIs occurred more frequently.

James F List - One of the best experts on this subject based on the ideXlab platform.

  • exploring the potential of the sglt2 inhibitor Dapagliflozin in type 1 diabetes a randomized double blind placebo controlled pilot study
    Diabetes Care, 2015
    Co-Authors: Robert R Henry, James F List, Sreeneeranj Kasichayanula, Nayyar Iqbal, Julio Rosenstock, Steven V Edelman, Sunder Mudaliar, Alexandrosgeorgios Chalamandaris, Allyson Bogle, Steven C Griffen
    Abstract:

    OBJECTIVE Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium–glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of Dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA 1c 7–10%), who were receiving treatment with stable doses of insulin, to one of four Dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0–92.3%); one major event of hypoglycemia occurred with Dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with Dapagliflozin 10 mg and decreased by −21.5 g/24 h (95% CI −53.9 to 11.0) with placebo. Changes from baseline with Dapagliflozin 10 mg by day 7 were as follows: −2.29 mmol/L (95% CI −3.71 to −0.87 [−41.3 mg/dL; 95% CI −66.9 to −15.7]) for 24-h daily average blood glucose; −3.77 mmol/L (95% CI −6.09 to −1.45 [−63.1 mg/dL; 95% CI −111.5 to −14.8]) for mean amplitude of glycemic excursion; and −16.2% (95% CI −29.4 to −0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: −1.13 mmol/L (95% CI −3.63 to 1.37), −0.45 mmol/L (95% CI −4.98 to 4.08), and 1.7% (95% CI −22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all Dapagliflozin doses overlapped those for placebo. CONCLUSIONS This exploratory study of Dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the Dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.

  • long term study of patients with type 2 diabetes and moderate renal impairment shows that Dapagliflozin reduces weight and blood pressure but does not improve glycemic control
    Kidney International, 2014
    Co-Authors: Donald E Kohan, Paola Fioretto, Weihua Tang, James F List
    Abstract:

    In patients with diabetes, glycemic improvement by sodium-glucose cotransporter-2 inhibition depends on the kidney's ability to filter glucose. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces hyperglycemia in patients with diabetes and normal or mildly impaired renal function. In this randomized, double-blind, placebo-controlled study we assessed daily treatment with Dapagliflozin in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment. The primary endpoint, the mean change in HbA1c, was not statistically different from placebo after 24 weeks (-0.41% and -0.44% for 5- and 10-mg doses, respectively, and -0.32% for placebo). The mean weight change from baseline was -1.54 and -1.89kg for the 5- and 10-mg doses, respectively, and +0.21kg for placebo. The mean systolic and diastolic blood pressure decreased in the Dapagliflozin groups compared to placebo. Through 104 weeks, 13 patients receiving Dapagliflozin and no patients receiving placebo experienced bone fracture. At 1 week, the mean serum creatinine increased with Dapagliflozin 5mg (+0.13mg/dl) and 10mg (+0.18mg/dl) and did not change further after 104 weeks. Mean serum electrolytes did not change in any group, and there were fewer episodes of hyperkalemia with Dapagliflozin than placebo. Thus, in patients with moderate renal impairment, Dapagliflozin did not improve glycemic control, but reduced weight and blood pressure.

  • Dapagliflozin add on to metformin in type 2 diabetes inadequately controlled with metformin a randomized double blind placebo controlled 102 week trial
    BMC Medicine, 2013
    Co-Authors: Clifford J Bailey, Nayyar Iqbal, Jorge Luiz Gross, Delphine Hennicken, Traci A Mansfield, James F List
    Abstract:

    Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, Dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate Dapagliflozin as long-term therapy in this population. This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or Dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight. A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the Dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for Dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all Dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of Dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (Dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of Dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (Dapagliflozin 2.5 mg). Dapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone. ClinicalTrials.gov: NCT00528879

  • Dapagliflozin metformin xr or both initial pharmacotherapy for type 2 diabetes a randomised controlled trial
    International Journal of Clinical Practice, 2012
    Co-Authors: Robert R Henry, A V Murray, M H Marmolejo, D Hennicken, Agata Ptaszynska, James F List
    Abstract:

    Summary Background:  Combining metformin (XR) with Dapagliflozin to initiate pharmacotherapy in patients with type 2 diabetes (T2D) and high baseline HbA1c may be advantageous. We conducted two randomised, double-blind, three-arm 24-week trials in treatment-naive patients to compare Dapagliflozin plus metformin, Dapagliflozin alone and metformin alone. Methods:  Eligible patients had baseline HbA1c 7.5–12%. Each trial had three arms: Dapagliflozin plus metformin, Dapagliflozin monotherapy and metformin monotherapy. Dapagliflozin in combination and as monotherapy was dosed at 5 mg (Study 1) and 10 mg (Study 2). Metformin in combination and as monotherapy was titrated to 2000 mg. The primary endpoint was HbA1c change from baseline; secondary endpoints included change in fasting plasma glucose (FPG) and weight. Results:  In both trials, combination therapy led to significantly greater reductions in HbA1c compared with either monotherapy: −2.05 for Dapagliflozin + metformin, −1.19 for Dapagliflozin, and −1.35 for metformin (p < 0.0001) (Study 1); −1.98 for Dapagliflozin + metformin, −1.45 for Dapagliflozin and −1.44 for metformin (p < 0.0001) (Study 2). Combination therapy was statistically superior to monotherapy in reduction of FPG (p < 0.0001 for both studies); combination therapy was more effective than metformin for weight reduction (p < 0.0001). Dapagliflozin 10 mg was non-inferior to metformin in reducing HbA1c (Study 2). Events suggestive of genital infection were reported in 6.7%, 6.9% and 2.0% (Study 1) and 8.5%, 12.8% and 2.4% (Study 2) of patients in combination, Dapagliflozin and metformin groups; events suggestive of urinary tract infection were reported in 7.7%, 7.9% and 7.5% (Study 1) and 7.6%, 11.0% and 4.3% (Study 2) of patients in the respective groups. No major hypoglycaemia was reported. Conclusion:  In treatment-naive patients with T2D, Dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c, FPG and weight. Dapagliflozin-induced glucosuria led to an increase in events suggestive of urinary tract and genital infections.

  • Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise a randomized double blind placebo controlled phase 3 trial
    Diabetes Care, 2010
    Co-Authors: Ele Ferrannini, Weihua Tang, Silvia Jimenez Ramos, Afshin Salsali, James F List
    Abstract:

    OBJECTIVE: Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of Dapagliflozin in treatment-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0-10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg Dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1-12% (high-A1C exploratory cohort; n = 73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day Dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA. RESULTS: In the main cohort, mean A1C changes from baseline at week 24 were -0.23% with placebo and -0.58, -0.77 (P = 0.0005 vs. placebo), and -0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg Dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the Dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results. CONCLUSIONS: Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make Dapagliflozin a unique addition to existing treatment options for type 2 diabetes.

S J Parikh - One of the best experts on this subject based on the ideXlab platform.

  • osmotic diuresis with sglt2 inhibition analysis of events related to volume reduction in Dapagliflozin clinical trials
    Postgraduate Medicine, 2016
    Co-Authors: Kristina Johnsson, Agata Ptaszynska, E Johnsson, T A Mansfield, Yshai Yavin, S J Parikh
    Abstract:

    ABSTRACTObjective: Dapagliflozin reduces hyperglycemia in type 2 diabetes mellitus (T2DM) and lowers blood pressure, at least in part, secondary to mild diuresis consequent to Dapagliflozin-induced glucosuria. While blood-pressure lowering may contribute to cardiovascular risk reduction, Dapagliflozin-induced diuresis may potentially contribute to adverse events (AEs) of volume reduction. The present analysis compared the frequency of AEs of volume reduction between Dapagliflozin and placebo.Methods: Pooled data were assessed from 13 placebo-controlled Dapagliflozin clinical trials ≤24 weeks in patients with T2DM, overall, and in those at risk (aged ≥65y, estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2, or on antihypertensive therapy). Longer-term (≤104 weeks) data were available for 9 of these trials.Results: The frequency of patients experiencing ≥1 AE of volume reduction over 24 weeks was low overall; 27/2360 (1.1%) with Dapagliflozin 10 mg and 17/2295 (0.7%) with placebo; and slightly m...

  • long term glycaemic response and tolerability of Dapagliflozin versus a sulphonylurea as add on therapy to metformin in patients with type 2 diabetes 4 year data
    Diabetes Obesity and Metabolism, 2015
    Co-Authors: S Del Prato, Santiago Durangarcia, K Rohwedder, Michael A Nauck, L Maffei, A Theuerkauf, S J Parikh
    Abstract:

    Aims To assess the long-term efficacy and tolerability of Dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Methods The present study was an extension of an earlier randomized, double-blind, phase III study of Dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. Results At 208 weeks, Dapagliflozin compared with glipizide produced sustained reductions in glycated haemoglogin (HbA1c): −0.30% [95% confidence interval (CI), −0.51 to −0.09], in total body weight: −4.38 kg (95% CI −5.31 to −3.46) and in systolic blood pressure (SBP): −3.67 mmHg (95% CI −5.92 to −1.41). The HbA1c coefficient of failure was significantly lower for Dapagliflozin than for glipizide: 0.19 (95% CI 0.12–0.25) versus 0.61 (95% CI 0.49–0.72, difference −0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in patients in the glipizide group. Fewer patients reported hypoglycaemia in the Dapagliflozin compared with the glipizide group (5.4 vs 51.5%). Genital and urinary tract infections were more common with Dapagliflozin than with glipizide, but their incidence decreased with time and all events responded well to antimicrobial treatment. Conclusions In patients completing 4 years of treatment, Dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide.

  • Dapagliflozin improves glycemic control and reduces body weight as add on therapy to metformin plus sulfonylurea a 24 week randomized double blind clinical trial
    Diabetes Care, 2015
    Co-Authors: Stephan Matthaei, K Rohwedder, Keith Bowering, Anke Grohl, S J Parikh
    Abstract:

    OBJECTIVE To evaluate the efficacy and safety of Dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin and sulfonylurea. RESEARCH DESIGN AND METHODS Patients with HbA1c of 7.0% (53 mmol/mol) to 10.5% (91 mmol/mol) receiving sulfonylurea and metformin were randomized to receive Dapagliflozin 10 mg/day ( n = 109) or placebo ( n = 109) for 24 weeks. RESULTS HbA1c (baseline: Dapagliflozin 8.08% [65 mmol/mol]; placebo 8.24% [67 mmol/mol]) and fasting plasma glucose (baseline: Dapagliflozin 167.4 mg/dL [9.29 mmol/L]; placebo 180.5 mg/dL [10.02 mmol/L]) significantly improved from baseline with Dapagliflozin (placebo-subtracted change –0.69% [–7.5 mmol/mol], P < 0.0001; –33.5 mg/dL [–1.86 mmol/L], P < 0.0001, respectively). More patients achieved a therapeutic glycemic response (HbA1c <7.0% [53 mmol/mol]) with Dapagliflozin (31.8%) versus placebo (11.1%) ( P < 0.0001). Body weight and systolic blood pressure were significantly reduced from baseline over 24 and 8 weeks, respectively, with Dapagliflozin (placebo-subtracted change –2.1 kg, P < 0.0001; –3.8 mmHg, P = 0.0250). Patients receiving Dapagliflozin showed placebo-subtracted increases in total, LDL, and HDL cholesterol (11.4 mg/dL, P = 0.0091; 11.4 mg/dL, P = 0.0030; 2.2 mg/dL, P = 0.0172, respectively) with no change in LDL/HDL cholesterol ratio (0.1; P = 0.2008) or triglycerides (–16.5 mg/dL; P = 0.1755). Adverse events occurred in 48.6% of patients receiving Dapagliflozin and 51.4% receiving placebo. Significantly more patients with Dapagliflozin compared with placebo experienced hypoglycemia (12.8 vs. 3.7%; P = 0.024) and genital infections (5.5 vs. 0%; P = 0.029). Events of urinary tract infection were reported by 6.4% of patients in both groups. CONCLUSIONS Dapagliflozin was well tolerated and effective over 24 weeks as add-on to metformin plus sulfonylurea. Adverse effects included hypoglycemia and genital infections.

  • durability of glycaemic efficacy over 2 years with Dapagliflozin versus glipizide as add on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin
    Diabetes Obesity and Metabolism, 2014
    Co-Authors: Michael A Nauck, Santiago Durangarcia, K Rohwedder, S Del Prato, Anna Maria Langkilde, Jennifer Sugg, S J Parikh
    Abstract:

    Aims To assess the long-term glycaemic durability, safety and tolerability of Dapagliflozin versus glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled by metformin alone. Methods This was a 52-week, randomised, double-blind study of Dapagliflozin (n = 406) versus glipizide (n = 408), uptitrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 and 20 mg/day, respectively, as add-on therapies to metformin (≥1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. Results In total, 53.1% of patients completed 104 weeks of treatment. After the greater initial decrease (0–18 weeks) in glycated haemoglobin (HbA1c) with glipizide, the 18–104-week HbA1c coefficient of failure (CoF) was lower with Dapagliflozin (0.13%/year) than with glipizide (0.59%/year), resulting in significant Dapagliflozin versus glipizide differences of −0.46%/year (95% CI −0.60,−0.33; p = 0.0001) for CoF and −0.18%(−2.0 mmol/mol) [95% CI −0.33(−3.6),−0.03(−0.3); p = 0.021] for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure, whereas glipizide increased weight and systolic blood pressure, giving 104-week Dapagliflozin versus glipizide differences of −5.1 kg (95% CI: −5.7,−4.4) and −3.9 mmHg (95% CI: −6.1,−1.7), respectively. Over 104 weeks, the hypoglycaemia rate was 10-fold lower with Dapagliflozin than with glipizide (4.2 vs. 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection (UTI) were greater with Dapagliflozin (14.8 and 13.5%, respectively) than with glipizide (2.9 and 9.1%, respectively). Conclusions Over 2 years, compared with glipizide, Dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and systolic blood pressure and a low hypoglycaemia rate; however, genital infections and UTIs occurred more frequently.

  • efficacy and safety of Dapagliflozin as a monotherapy for type 2 diabetes mellitus in japanese patients with inadequate glycaemic control a phase ii multicentre randomized double blind placebo controlled trial
    Diabetes Obesity and Metabolism, 2013
    Co-Authors: Kohei Kaku, Anna Maria Langkilde, S Inoue, O Matsuoka, Arihiro Kiyosue, H Azuma, N Hayashi, Takuto Tokudome, S J Parikh
    Abstract:

    Aim Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of Dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. Methods Patients (n = 279) were randomized to receive Dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c <7.0% at week 12. Results Significant reductions in HbA1c were seen with all Dapagliflozin doses (−0.11 to −0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with Dapagliflozin (−0.87 to −1.77 mmol/l [−15.61 to −31.94 mg/dl]) versus placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with Dapagliflozin versus placebo. Adverse events (AEs) were more frequent with Dapagliflozin (40.7–53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, Dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0–3.8 and 0–1.8% respectively with Dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed. Conclusions Compared with placebo, Dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.

Nayyar Iqbal - One of the best experts on this subject based on the ideXlab platform.

  • benefit risk profile of Dapagliflozin 5 mg in the depict 1 and 2 trials in individuals with type 1 diabetes and body mass index 27 kg m2
    Diabetes Obesity and Metabolism, 2020
    Co-Authors: Chantal Mathieu, Nayyar Iqbal, P Dandona, Andreas L Birkenfeld, Troels Krarup Hansen, Enrico Repetto, Markus F Scheerer, Fredrik Thoren, Moshe Phillip
    Abstract:

    Aim The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of Dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of Dapagliflozin in individuals with type 1 diabetes. This post-hoc study investigated the safety and efficacy of Dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with Dapagliflozin treatment can be further improved than that observed in the overall DEPICT population. Methods Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56. Results Week-52 adjusted mean (SE) change from baseline for HbA1c was -0.26% (0.05) with Dapagliflozin versus +0.08% (0.05) with placebo and for body weight was -2.74 kg (0.25) with Dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was -10.5% (1.23) with Dapagliflozin versus -1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (Dapagliflozin, 1.7%; placebo, 1.0%) than Dapagliflozin 5 mg receiving participants in the pooled DEPICT populations. Conclusions Compared with the pooled DEPICT population, the benefit/risk profile of adjunct Dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

  • effect of Dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes post hoc renal analysis of the depict randomised controlled trials
    The Lancet Diabetes & Endocrinology, 2020
    Co-Authors: Perhenrik Groop, Nayyar Iqbal, Steven V Edelman, P Dandona, Markus F Scheerer, Fredrik Thoren, Moshe Phillip, Pieter Gillard, Johan Jendle, Enrico Repetto
    Abstract:

    Summary Background The DEPICT-1 and DEPICT-2 studies showed that Dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of Dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. Methods In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18–75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive Dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov , NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. Results 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to Dapagliflozin 5 mg, 84 (33%) to Dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both Dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was −13·3% (95% CI −37·2 to 19·8) for Dapagliflozin 5 mg and −31·1% (−49·9 to −5·2) for Dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI −0·92 to 7·45) for Dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (–2·03 to 6·27) for Dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. Interpretation Treatment with Dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. Funding AstraZeneca.

  • safety and tolerability of Dapagliflozin saxagliptin and metformin in combination post hoc analysis of concomitant add on versus sequential add on to metformin and of triple versus dual therapy with metformin
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Stefano Del Prato, E Johnsson, Ricardo Garciasanchez, Nayyar Iqbal, Julio Rosenstock, Lars Hansen, Hungta Chen, Chantal Mathieu
    Abstract:

    The safety of triple oral therapy with Dapagliflozin plus saxagliptin plus metformin versus dual therapy with Dapagliflozin or saxagliptin plus metformin was compared in a post-hoc analysis of 3 randomized trials of sequential or concomitant add-on of Dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received Dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/d or Dapagliflozin 10 mg/d received Dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add-on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of Dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with Dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add-on, were similar to dual therapy with either agent added to metformin.

  • efficacy and safety of triple therapy with Dapagliflozin add on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes
    Diabetes Obesity and Metabolism, 2016
    Co-Authors: Chantal Mathieu, E Johnsson, Ricardo Garciasanchez, Lars Hansen, Hungta Chen, Herrera M Marmolejo, J Gonzalez G Gonzalez, Nayyar Iqbal
    Abstract:

    We previously reported that Dapagliflozin versus placebo as add-on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open-label metformin and saxagliptin 5 mg/day for 8-16 weeks were randomized to placebo or Dapagliflozin 10 mg/day plus open-label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with Dapagliflozin versus placebo in A1C (−0.74% vs. 0.07%), FPG (−27 vs. 10 mg/dL) and BW (−2.1 vs. −0.4 kg). More patients achieved A1C <7% with Dapagliflozin (29.4%) versus placebo (12.6%). Adverse events were similar with Dapagliflozin (66%) and placebo (71%), and hypoglycaemia was rare (≤2%). Genital infections occurred more often with Dapagliflozin (6%) than with placebo (1%); frequency of urinary tract infections was similar between the two groups (9% vs. 10%). Triple therapy with Dapagliflozin add-on to saxagliptin plus metformin is a durable, effective and well-tolerated intervention for the treatment of T2D.

  • randomized double blind trial of triple therapy with saxagliptin add on to Dapagliflozin plus metformin in patients with type 2 diabetes
    Diabetes Care, 2015
    Co-Authors: Stephan Matthaei, Nayyar Iqbal, Hungta Chen, Doina Catrinoiu, Aleksander Celinski, Ella Ekholm, William Cook, Boaz Hirshberg, Lars Hansen
    Abstract:

    OBJECTIVE The objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to Dapagliflozin plus metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients on stable metformin (≥1,500 mg/day) for ≥8 weeks with glycated hemoglobin (HbA1c) 8.0–11.5% (64–102 mmol/mol) at screening received open-label Dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA1c 7–10.5% [53–91 mmol/mol]) were then randomized to receive placebo ( n = 153) or saxagliptin 5 mg/day ( n = 162) in addition to background Dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA1c from baseline to week 24. RESULTS There was a significantly greater reduction in HbA1c at 24 weeks with saxagliptin add-on (–0.51% [–5.6 mmol/mol]) versus placebo (–0.16% [–1.7 mmol/mol]) add-on to Dapagliflozin plus metformin (difference, –0.35% [95% CI –0.52% to –0.18%] and –3.8 [–5.7 to –2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to Dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia. CONCLUSIONS Triple therapy with the addition of saxagliptin to Dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with type 2 diabetes inadequately controlled with Dapagliflozin plus metformin.

Sreeneeranj Kasichayanula - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes
    2016
    Co-Authors: Ralph A. Defronzo, Sreeneeranj Kasichayanula, Xiaoni Liu, Marc Pfister, David W Boulton, Bruce R Leslie, Marcus Hompesch, Ying Hong, Linda A. Morrow, Agatha Ching
    Abstract:

    OBJECTIVEdTo examine the effect of Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased TmG, increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODSdSubjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of Dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTSdAt baseline, type 2 diabetic subjects had elevated maximum renal glucose reab-sorptive capacity (TmG), splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of Dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONdThe SGLT2 inhibitor Dapagliflozin improves glycemic control in diabeti

  • Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and SubjectsWith Type 2 Diabetes
    2016
    Co-Authors: Ralph A. Defronzo, Sreeneeranj Kasichayanula, Xiaoni Liu, Marc Pfister, David W Boulton, Bruce R Leslie, Marcus Hompesch, Ying Hong, Linda A. Morrow, Agatha Ching
    Abstract:

    OBJECTIVEdTo examine the effect of Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on themajor components of renal glucose reabsorption (decreasedmaximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODSdSubjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of Dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTSdAt baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold com-pared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. How-ever, the most significant effect of Dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONSdThe SGLT2 inhibitor Dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine

  • exploring the potential of the sglt2 inhibitor Dapagliflozin in type 1 diabetes a randomized double blind placebo controlled pilot study
    Diabetes Care, 2015
    Co-Authors: Robert R Henry, James F List, Sreeneeranj Kasichayanula, Nayyar Iqbal, Julio Rosenstock, Steven V Edelman, Sunder Mudaliar, Alexandrosgeorgios Chalamandaris, Allyson Bogle, Steven C Griffen
    Abstract:

    OBJECTIVE Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium–glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of Dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA 1c 7–10%), who were receiving treatment with stable doses of insulin, to one of four Dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0–92.3%); one major event of hypoglycemia occurred with Dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with Dapagliflozin 10 mg and decreased by −21.5 g/24 h (95% CI −53.9 to 11.0) with placebo. Changes from baseline with Dapagliflozin 10 mg by day 7 were as follows: −2.29 mmol/L (95% CI −3.71 to −0.87 [−41.3 mg/dL; 95% CI −66.9 to −15.7]) for 24-h daily average blood glucose; −3.77 mmol/L (95% CI −6.09 to −1.45 [−63.1 mg/dL; 95% CI −111.5 to −14.8]) for mean amplitude of glycemic excursion; and −16.2% (95% CI −29.4 to −0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: −1.13 mmol/L (95% CI −3.63 to 1.37), −0.45 mmol/L (95% CI −4.98 to 4.08), and 1.7% (95% CI −22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all Dapagliflozin doses overlapped those for placebo. CONCLUSIONS This exploratory study of Dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the Dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.

  • clinical pharmacokinetics and pharmacodynamics of Dapagliflozin a selective inhibitor of sodium glucose co transporter type 2
    Clinical Pharmacokinectics, 2014
    Co-Authors: Sreeneeranj Kasichayanula, Xiaoni Liu, Steven C Griffen, Frank Lacreta, David W Boulton
    Abstract:

    Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered Dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to Dapagliflozin has been observed over a wide dose range (0.1–500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite Dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent). Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a Dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered Dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in Dapagliflozin exposure with respect to age, race, sex, body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma glucose and renal function, and decreases in urinary glucose excretion were observed due to the lower filtered load (plasma glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of Dapagliflozin, urinary glucose excretion was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to Dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of Dapagliflozin when administered with other antidiabetic or cardiovascular medications, as well as drugs that could potentially influence Dapagliflozin metabolism.

  • the influence of kidney function on Dapagliflozin exposure metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus
    British Journal of Clinical Pharmacology, 2013
    Co-Authors: Sreeneeranj Kasichayanula, Xiaoni Liu, Marc Pfister, Frank Lacreta, Melanie Pe Benito, Ming Yao, William G Humphreys, David W Boulton
    Abstract:

    Aim(s) This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of Dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Methods A single 50 mg dose of Dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of Dapagliflozin were evaluated in the patients with T2DM. Formation rates of Dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes. Results Plasma concentrations of Dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for Dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively. Conclusions These results indicate that both kidney and liver significantly contribute to Dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.

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