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Julio Rosenstock - One of the best experts on this subject based on the ideXlab platform.

  • low Dose empagliflozin as adjunct to Insulin therapy in type 1 diabetes a valid modelling and simulation analysis to confirm efficacy
    Diabetes Obesity and Metabolism, 2020
    Co-Authors: Julio Rosenstock, Lori M Laffel, Bruce A Perkins, Nima Soleymanlou, Jay S Skyler, Karlheinz Liesenfeld, Dietmar Neubacher, Matthew M Riggs, Curtis K Johnston
    Abstract:

    Aim To confirm the observed reduction in HbA1c for the 2.5 mg Dose in EASE-3 by modelling and simulation analyses. Materials and methods Independent of data from EASE-3 that tested 2.5 mg, we simulated the effect of a 2.5 mg Dose through patient-level, exposure-response modelling in the EASE-2 clinical study. A primary semi-mechanistic model evaluated efficacy considering clinical Insulin Dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, Insulin Dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE-3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE-3 but not EASE-2) included a lower 2.5 mg Dose. A placebo-corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher Doses (10 mg and 25 mg). Since only one trial included the lower Dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg Dose by modelling and simulation analyses. Results The simulated 26-week mean HbA1c change was -0.41% without Insulin Dose adjustment and -0.29% at 26 weeks with Insulin Dose adjustment. A simplified (descriptive) model excluding Insulin Dose and mean daily glucose confirmed the -0.29% HbA1c change that would have been observed had the EASE-2 population received a 2.5 mg Dose for 26/52 weeks. Conclusions The HbA1c benefit of low-Dose empagliflozin directly observed in the EASE-3 trial was confirmed by two modelling and simulation approaches.

  • sotagliflozin in combination with optimized Insulin therapy in adults with type 1 diabetes the north american intandem1 study
    Diabetes Care, 2018
    Co-Authors: John B Buse, Timothy S Bailey, Julio Rosenstock, Thomas Danne, Bruce W Bode, Satish K Garg, Phillip Banks, Jake A Kushner, Wendy Lane, Pablo Lapuerta
    Abstract:

    OBJECTIVE Evaluate the efficacy and safety of the dual sodium–glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized Insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo ( n = 268), sotagliflozin 200 mg ( n = 263), or sotagliflozin 400 mg ( n = 262) after 6 weeks of Insulin optimization. The primary end point was HbA 1c change from baseline at 24 weeks. HbA 1c , weight, and safety were also assessed through 52 weeks. RESULTS From a mean baseline of 7.57%, placebo-adjusted HbA 1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P 1c ≥7.0%, an HbA 1c P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were −1.08 mmol/L for fasting plasma glucose, −4.32 kg for weight, and −15.63% for bolus Insulin Dose and −11.87% for basal Insulin Dose (all P P CONCLUSIONS In a 1-year T1D study, sotagliflozin combined with optimized Insulin therapy was associated with sustained HbA 1c reduction, weight loss, lower Insulin Dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (NCT02384941).

  • impact of empagliflozin added on to basal Insulin in type 2 diabetes inadequately controlled on basal Insulin a 78 week randomized double blind placebo controlled trial
    Diabetes Obesity and Metabolism, 2015
    Co-Authors: Julio Rosenstock, Uli C Broedl, G Kim, Cordula Zeller, Ante Jelaska, Hansjuergen Woerle
    Abstract:

    Aims To investigate the efficacy and tolerability of empagliflozin added to basal Insulin-treated type 2 diabetes. Methods Patients inadequately controlled [glycated haemoglobin (HbA1c) >7 to ≤10% (>53 to ≤86 mmol/mol)] on basal Insulin (glargine, detemir, NPH) were randomized to empagliflozin 10 mg (n = 169), empagliflozin 25 mg (n = 155) or placebo (n = 170) for 78 weeks. The baseline characteristics were balanced among the groups [mean HbA1c 8.2% (67 mmol/mol), BMI 32.2 kg/m2]. The basal Insulin Dose was to remain constant for 18 weeks, then could be adjusted at investigator's discretion. The primary endpoint was change from baseline in HbA1c at week 18. Key secondary endpoints were changes from baseline in HbA1c and Insulin Dose at week 78. Results At week 18, the adjusted mean ± standard error changes from baseline in HbA1c were 0.0 ± 0.1% (−0.1 ± 0.8 mmol/mol) for placebo, compared with −0.6 ± 0.1% (−6.2 ± 0.8 mmol/mol) and −0.7 ± 0.1% (−7.8 ± 0.8 mmol/mol) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). At week 78, empagliflozin 10 and 25 mg significantly reduced HbA1c, Insulin Dose and weight vs placebo (all p < 0.01), and empagliflozin 10 mg significantly reduced systolic blood pressure vs placebo (p = 0.004). Similar percentages of patients had confirmed hypoglycaemia in all groups (35–36%). Events consistent with urinary tract infection were reported in 9, 15 and 12% of patients on placebo, empagliflozin 10 and 25 mg, and events consistent with genital infection were reported in 2, 8 and 5%, respectively. Conclusions Empagliflozin for 78 weeks added to basal Insulin improved glycaemic control and reduced weight with a similar risk of hypoglycaemia to placebo.

  • sotagliflozin a dual sglt1 and sglt2 inhibitor as adjunct therapy to Insulin in type 1 diabetes
    Diabetes Care, 2015
    Co-Authors: Arthur T Sands, Julio Rosenstock, Bruce W Bode, John B Buse, Brian Zambrowicz, Pablo Lapuerta, Satish K Garg, Phillip Banks, Rubina A Heptulla, Marc Rendell
    Abstract:

    OBJECTIVE To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to Insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, Insulin Dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus Insulin Dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus Insulin Dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70–180 mg/dL (3.9–10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS As adjunct to Insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus Insulin Dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.

  • 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, Julio Rosenstock, Steven V Edelman, Sunder Mudaliar, Alexandrosgeorgios Chalamandaris, Sreeneeranj Kasichayanula, Allyson Bogle, Nayyar Iqbal, James F List, 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.

Daniel J West - One of the best experts on this subject based on the ideXlab platform.

  • Insulin therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia after evening exercise in type 1 diabetes: a randomized controlled trial
    BMJ Open Diabetes Research & Care, 2015
    Co-Authors: Matthew Campbell, Javier T Gonzalez, Emma J Stevenson, Mark Walker, James A.m. Shaw, Richard M. Bracken, Daniel Turner, Daniel J West
    Abstract:

    Introduction: Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus Insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus Insulin Dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. Methods: Ten male participants (glycated hemoglobin: 52.4±2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal Insulin Dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ∼08:00 h for a fasted blood sample, before returning in the evening. On arrival (∼17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting Insulin Dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting Insulin Dose, before returning home. At ∼23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (∼08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, βhydroxybutyrate, interleukin 6, and tumor necrosis factor α. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. Results: Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24 h postexercise. All metabolic parameters were similar.

  • comparison of appetite responses to high and low glycemic index postexercise meals under matched Insulinemia and fiber in type 1 diabetes
    The American Journal of Clinical Nutrition, 2015
    Co-Authors: Matthew Campbell, Javier T Gonzalez, Penny L S Rumbold, Emma J Stevenson, James Shaw, Mark Walker, Daniel J West
    Abstract:

    BACKGROUND: Patients with type 1 diabetes face heightened risk of hypoglycemia after exercise. Subsequent overfeeding, as a preventative measure against hypoglycemia, negates the energy deficit after exercise. Patients are also required to reduce the Insulin Dose administered with postexercise foods to further combat hypoglycemia. However, the Insulin Dose is dictated solely by the carbohydrate content, even though postprandial glycemia is vastly influenced by glycemic index (GI). With a need to control the postexercise energy balance, appetite responses after meals differing in GI are of particular interest. OBJECTIVES: We assessed the appetite response to low-glycemic index (LGI) and high-glycemic index (HGI) postexercise meals in type 1 diabetes patients. This assessment also offered us the opportunity to evaluate the influence of GI on appetite responses independently of Insulinemia, which confounds findings in individuals without diabetes. DESIGN: Ten physically active men with type 1 diabetes completed 2 trials in a randomized crossover design. After 45 min of treadmill exercise at 70% of the peak oxygen uptake, participants consumed an LGI (GI ∼37) or HGI (GI ∼92) meal with a matched macronutrient composition, negligible fiber content, and standardized Insulin-Dose administration. The postprandial appetite response was determined for 180 min postmeal. During this time, circulating glucose, Insulin, glucagon, and glucagon-like peptide-1 (GLP-1) concentrations and subjective appetite ratings were determined. RESULTS: The HGI meal produced an ∼60% greater postprandial glucose area under the curve (AUC) than did the LGI meal (P = 0.008). Insulin, glucagon, and GLP-1 did not significantly differ between trials (P > 0.05). The fullness AUC was ∼25% greater after the HGI meal than after the LGI meal (P < 0.001), whereas hunger sensations were ∼9% lower after the HGI meal than after the LGI meal (P = 0.001). CONCLUSION: Under conditions of matched Insulinemia and fiber, an HGI postexercise meal suppresses feelings of hunger and augments postprandial fullness sensations more so than an otherwise equivalent LGI meal in type 1 diabetes patients.

  • a low glycemic index meal and bedtime snack prevents postprandial hyperglycemia and associated rises in inflammatory markers providing protection from early but not late nocturnal hypoglycemia following evening exercise in type 1 diabetes
    Diabetes Care, 2014
    Co-Authors: Matthew Campbell, Emma J Stevenson, Mark Walker, James A.m. Shaw, Richard M. Bracken, Daniel Turner, Michael I Trenell, Daniel J West
    Abstract:

    OBJECTIVE To examine the influence of the glycemic index (GI) of foods consumed after evening exercise on postprandial glycemia, metabolic and inflammatory markers, and nocturnal glycemic control in type 1 diabetes. RESEARCH DESIGN AND METHODS On two evenings (∼1700 h), 10 male patients (27 ± 5 years of age, HbA 1c 6.7 ± 0.7% [49.9 ± 8.1 mmol/mol]) were administered a 25% rapid-acting Insulin Dose with a carbohydrate bolus 60 min before 45 min of treadmill running. At 60 min postexercise, patients were administered a 50% rapid-acting Insulin Dose with one of two isoenergetic meals (1.0 g carbohdyrate/kg body mass [BM]) matched for macronutrient content but of either low GI (LGI) or high GI (HGI). At 180 min postmeal, the LGI group ingested an LGI snack and the HGI group an HGI snack (0.4 g carbohdyrate/kg BM) before returning home (∼2300 h). Interval samples were analyzed for blood glucose and lactate; plasma glucagon, epinephrine, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); and serum Insulin, cortisol, nonesterified fatty acid, and β-hydroxybutyrate concentrations. Interstitial glucose was recorded for 20 h postlaboratory attendance through continuous glucose monitoring. RESULTS Following the postexercise meal, an HGI snack induced hyperglycemia in all patients (mean ± SD glucose 13.5 ± 3.3 mmol/L) and marked increases in TNF-α and IL-6, whereas relative euglycemia was maintained with an LGI snack (7.7 ± 2.5 mmol/L, P n = 5 for both HGI and LGI). CONCLUSIONS Consuming LGI food with a reduced rapid-acting Insulin Dose following evening exercise prevents postprandial hyperglycemia and inflammation and provides hypoglycemia protection for ∼8 h postexercise; however, the risk of late nocturnal hypoglycemia remains.

  • large pre and postexercise rapid acting Insulin reductions preserve glycemia and prevent early but not late onset hypoglycemia in patients with type 1 diabetes
    Diabetes Care, 2013
    Co-Authors: Matthew Campbell, Emma J Stevenson, Mark Walker, Richard M. Bracken, Michael I Trenell, Djordje G Jakovljevic, Stephen C Bain, Daniel J West
    Abstract:

    OBJECTIVE To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting Insulin Dose in type 1 diabetic patients. RESEARCH DESIGN AND METHODS After preliminary testing, 11 male patients (24 ± 2 years, HbA 1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg −1 BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting Insulin Dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO 2peak . At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg −1 BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting Insulin Dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system. RESULTS All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L −1 ], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions. CONCLUSIONS A 25% pre-exercise and 50% postexercise rapid-acting Insulin Dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia.

  • a combined Insulin reduction and carbohydrate feeding strategy 30 min before running best preserves blood glucose concentration after exercise through improved fuel oxidation in type 1 diabetes mellitus
    Journal of Sports Sciences, 2011
    Co-Authors: Daniel J West, Stephen C Bain, Jeffrey W Stephens, Liam P Kilduff, S D Luzio, Rachel Still, Richard M. Bracken
    Abstract:

    In this study, we examined the glycaemic and fuel oxidation responses to alterations in the timing of a low glycaemic index carbohydrate and 75% reduced Insulin Dose, prior to running, in type 1 diabetes individuals. After carbohydrate (75 g isomaltulose) and Insulin administration, the seven participants rested for 30 min, 60 min, 90 min or 120 min (conditions 30MIN, 60MIN, 90MIN, and 120MIN, respectively) before completing 45 min of running at 70% peak oxygen uptake. Carbohydrate and lipid oxidation rates were monitored during exercise and blood glucose and Insulin were measured before and for 3 h after exercise. Data were analysed using repeated-measures analysis of variance. Pre-exercise blood glucose concentrations were lower for 30MIN compared with 120MIN (P < 0.05), but Insulin concentrations were similar. Exercising carbohydrate and lipid oxidation rates were lower and greater, respectively, for 30MIN compared with 120MIN (P < 0.05). The drop in blood glucose during exercise was less for 30MIN (3.7 mmol · l−1, s[xbar] = 0.4) compared with 120MIN (6.4 mmol · l−1, s[xbar] = 0.3) (P = 0.02). For 60 min post-exercise, blood glucose concentrations were higher for 30MIN compared with 120MIN (P < 0.05). There were no cases of hypoglycaemia in the 30MIN condition, one case in the 60MIN condition, two in the 90MIN condition, and five in the 120MIN condition. In conclusion, a low glycaemic index carbohydrate and reduced Insulin Dose administered 30 min before running improves pre- and post-exercise blood glucose responses in type 1 diabetes.

Steven V Edelman - 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, Julio Rosenstock, Steven V Edelman, Sunder Mudaliar, Alexandrosgeorgios Chalamandaris, Sreeneeranj Kasichayanula, Allyson Bogle, Nayyar Iqbal, James F List, 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.

  • Insulin pump therapy in patients with type 2 diabetes safely improved glycemic control using a simple Insulin dosing regimen
    Diabetes Technology & Therapeutics, 2010
    Co-Authors: Steven V Edelman, Timothy S Bailey, Bruce W Bode, Mark S Kipnes, Rocco Brunelle, Xiaojing Chen, Juan P Frias
    Abstract:

    Abstract Background: This study assessed Insulin Dose and dosing patterns required to optimize glycemic control with an Insulin pump in patients with type 2 diabetes. Methods: In this 16-week, open-label, multicenter, pilot study, 56 Insulin pump-naive patients treated at baseline with two or more oral antidiabetes agents (OADs), basal Insulin with or without OADs, or basal-bolus Insulin with or without OADs discontinued all diabetes medications except metformin and initiated Insulin pump therapy. Insulin Doses were adjusted to optimize glycemic control with the simplest possible Insulin regimen. Outcomes included total daily Insulin Dose, daily basal and bolus Insulin Doses, number of daily basal rates, hemoglobin A1C, fasting and postprandial glucose, patient-reported outcomes and rate of hypoglycemia. Results: After 16 weeks of pump therapy, the mean ± SD total daily Insulin Dose was 95 ± 59 U. The percentage of the total daily Insulin Dose used as basal and as bolus delivery was 55% and 45%, respectiv...

  • significant Insulin Dose errors may occur if blood glucose results are obtained from miscoded meters
    Journal of diabetes science and technology, 2007
    Co-Authors: Charles H Raine, Linda E Schrock, Steven V Edelman, Sunder Mudaliar, Weiping Zhong, Lois J Proud, Joan Lee Parkes
    Abstract:

    Objective:The objective of this study was to determine inaccuracies of miscoded blood glucose (BG) meters and potential errors in Insulin Dose based on values from these meters.Research Design:Fasting diabetic subjects at three clinical centers participated in a 2-hour meal tolerance test. At various times subjects' blood was tested on five BG meters and on a Yellow Springs Instruments laboratory glucose analyzer. Some meters were purposely miscoded. Using the BG values from these meters, along with three Insulin Dose algorithms, Monte Carlo simulations were conducted to generate ideal and simulated-meter glucose values and subsequent probability of Insulin Dose errors based on normal and empirical distribution assumptions.Results:Maximal median percentage biases of miscoded meters were +29% and −37%, while maximal median percentage biases of correctly coded meters were only +0.64% and −10.45% (p = 0.000, χ2 test, df = 1). Using the low-Dose algorithm and the normal distribution assumption, the combined d...

Hannele Ykijarvinen - One of the best experts on this subject based on the ideXlab platform.

  • hepatic fat content and Insulin action on free fatty acids and glucose metabolism rather than Insulin absorption are associated with Insulin requirements during Insulin therapy in type 2 diabetic patients
    Diabetes, 2000
    Co-Authors: Leena Ryysy, Jukka Westerbacka, Annamaija Hakkinen, Takashi Goto, Satu Vehkavaara, Juha Halavaara, Hannele Ykijarvinen
    Abstract:

    To determine causes of interindividual variation in Insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and Insulin Doses for >1 year on combination therapy with bedtime NPH Insulin and metformin. Insulin absorption (increase in free and total Insulin over 8 h after a subcutaneous Dose of regular Insulin) and actions of intravenous (6-h 0.3 mU x kg(-1) x min(-1) euglycemic Insulin clamp combined with [3-3H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) Insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: Insulin Dose range 10-176 U (mean 42 U, fold variation 17.6x) or 0.13-1.39 U/kg (0.44 U/kg, 10.7x), absorbed Insulin 10.6x, action of subcutaneous Insulin to suppress FFAs 7.5 x and to stimulate glucose metabolism (M value) 11.5x, body weight 67-127 kg (91 kg, 1.9x), liver fat 2-28% (12%, 14x), and visceral fat 179-2,053 ml (1,114 ml, 11.5x). The amount of Insulin absorbed, measured as either free or total Insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the Insulin Dose per se. The actions of absorbed Insulin were, on the other hand, significantly correlated with the daily Insulin Dose (r = 0.70 for action on FFAs, P

  • hepatic fat content and Insulin action on free fatty acids and glucose metabolism rather than Insulin absorption are associated with Insulin requirements during Insulin therapy in type 2 diabetic patients
    Diabetes, 2000
    Co-Authors: Leena Ryysy, Jukka Westerbacka, Annamaija Hakkinen, Takashi Goto, Satu Vehkavaara, Juha Halavaara, Hannele Ykijarvinen
    Abstract:

    To determine causes of interindividual variation in Insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and Insulin Doses for >1 year on combination therapy with bedtime NPH Insulin and metformin. Insulin absorption (increase in free and total Insulin over 8 h after a subcutaneous Dose of regular Insulin) and actions of intravenous (6-h 0.3 mU x kg(-1) x min(-1) euglycemic Insulin clamp combined with [3-3H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) Insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: Insulin Dose range 10-176 U (mean 42 U, fold variation 17.6x) or 0.13-1.39 U/kg (0.44 U/kg, 10.7x), absorbed Insulin 10.6x, action of subcutaneous Insulin to suppress FFAs 7.5 x and to stimulate glucose metabolism (M value) 11.5x, body weight 67-127 kg (91 kg, 1.9x), liver fat 2-28% (12%, 14x), and visceral fat 179-2,053 ml (1,114 ml, 11.5x). The amount of Insulin absorbed, measured as either free or total Insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the Insulin Dose per se. The actions of absorbed Insulin were, on the other hand, significantly correlated with the daily Insulin Dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous Insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily Insulin Dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous Insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in Insulin requirements in type 2 diabetes is the variation in Insulin action. Variation in hepatic fat content may influence Insulin requirements via an effect on the sensitivity of endogenous glucose production to Insulin.

Hansjuergen Woerle - One of the best experts on this subject based on the ideXlab platform.

  • impact of empagliflozin added on to basal Insulin in type 2 diabetes inadequately controlled on basal Insulin a 78 week randomized double blind placebo controlled trial
    Diabetes Obesity and Metabolism, 2015
    Co-Authors: Julio Rosenstock, Uli C Broedl, G Kim, Cordula Zeller, Ante Jelaska, Hansjuergen Woerle
    Abstract:

    Aims To investigate the efficacy and tolerability of empagliflozin added to basal Insulin-treated type 2 diabetes. Methods Patients inadequately controlled [glycated haemoglobin (HbA1c) >7 to ≤10% (>53 to ≤86 mmol/mol)] on basal Insulin (glargine, detemir, NPH) were randomized to empagliflozin 10 mg (n = 169), empagliflozin 25 mg (n = 155) or placebo (n = 170) for 78 weeks. The baseline characteristics were balanced among the groups [mean HbA1c 8.2% (67 mmol/mol), BMI 32.2 kg/m2]. The basal Insulin Dose was to remain constant for 18 weeks, then could be adjusted at investigator's discretion. The primary endpoint was change from baseline in HbA1c at week 18. Key secondary endpoints were changes from baseline in HbA1c and Insulin Dose at week 78. Results At week 18, the adjusted mean ± standard error changes from baseline in HbA1c were 0.0 ± 0.1% (−0.1 ± 0.8 mmol/mol) for placebo, compared with −0.6 ± 0.1% (−6.2 ± 0.8 mmol/mol) and −0.7 ± 0.1% (−7.8 ± 0.8 mmol/mol) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). At week 78, empagliflozin 10 and 25 mg significantly reduced HbA1c, Insulin Dose and weight vs placebo (all p < 0.01), and empagliflozin 10 mg significantly reduced systolic blood pressure vs placebo (p = 0.004). Similar percentages of patients had confirmed hypoglycaemia in all groups (35–36%). Events consistent with urinary tract infection were reported in 9, 15 and 12% of patients on placebo, empagliflozin 10 and 25 mg, and events consistent with genital infection were reported in 2, 8 and 5%, respectively. Conclusions Empagliflozin for 78 weeks added to basal Insulin improved glycaemic control and reduced weight with a similar risk of hypoglycaemia to placebo.

  • improved glucose control with weight loss lower Insulin Doses and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of Insulin in obese inadequately controlled type 2 diabetes
    Diabetes Care, 2014
    Co-Authors: Julio Rosenstock, Hansjuergen Woerle, Afshin Salsali, G Kim, Ante Jelaska, Guillaume Frappin, Uli C Broedl
    Abstract:

    OBJECTIVE We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of Insulin (MDI Insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Patients inadequately controlled on MDI Insulin ± metformin (mean HbA1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m2; Insulin Dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg ( n = 186), empagliflozin 25 mg ( n = 189), or placebo ( n = 188) for 52 weeks. Insulin Dose was to remain stable in weeks 1–18, adjusted to meet glucose targets in weeks 19–40, then stable in weeks 41–52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in Insulin Dose, weight, and HbA1c at week 52. RESULTS Adjusted mean ± SE changes from baseline in HbA1c were −0.50 ± 0.05% (−5.5 ± 0.5 mmol/mol) for placebo versus −0.94 ± 0.05% (−10.3 ± 0.5 mmol/mol) and −1.02 ± 0.05% (−11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with Insulin titration resulted in changes from baseline in HbA1c of −0.81 ± 0.08% (−8.9 ± 0.9 mmol/mol), −1.18 ± 0.08% (−12.9 ± 0.9 mmol/mol), and −1.27 ± 0.08% (−13.9 ± 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c <7% (<53 mmol/mol) with empagliflozin (31–42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced Insulin Doses (−9 to −11 international units/day) and weight (−2.4 to −2.5 kg) versus placebo (all P < 0.01) at week 52. CONCLUSIONS In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI Insulin Doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower Insulin requirements.