Dallas Diabetes and Endocrine Center

Dallas, TX, United States

Dallas Diabetes and Endocrine Center

Dallas, TX, United States
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Rosenstock J.,Dallas Diabetes and Endocrine Center | Balas B.,Hoffmann-La Roche | Charbonnel B.,University of Nantes | Bolli G.B.,University of Perugia | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVEdTaspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide. RESEARCH DESIGN AND METHODSdOverweight adults with inadequately controlled type 2 diabetes on metformin 6 a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 mg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA1c after 24 weeks. RESULTSdMean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c significantly more than exenatide (taspoglutide 10 mg:-1.24%[SE 0.09], difference-0.26, 95%CI-0.37 to-0.15, P < 0.0001; taspoglutide 20 mg:-1.31% [0.08], difference-0.33,-0.44 to-0.22, P < 0.0001; exenatide:-0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg,-1.6 kg; taspoglutide 20 mg,-2.3 kg) as did exenatide (-2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA1c and weight effects were maintained after 52 weeks. More adverse eventswith taspoglutide 10 and 20mgthan exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients. CONCLUSIONSdOnce-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions. Copyright © 2013 by the American Diabetes Association.

Sands A.T.,Lexicon Pharmaceuticals Inc. | Zambrowicz B.P.,Lexicon Pharmaceuticals Inc. | Rosenstock J.,Dallas Diabetes and Endocrine Center | Lapuerta P.,Lexicon Pharmaceuticals Inc. | And 8 more authors.
Diabetes Care | Year: 2015

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. © 2015 by the American Diabetes Association.

Riddle M.,Oregon Health And Science University | Umpierrez G.,Emory University | Digenio A.,Sanofi S.A. | Zhou R.,Medpace | Rosenstock J.,Dallas Diabetes and Endocrine Center
Diabetes Care | Year: 2011

OBJECTIVE - To determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy. RESEARCH DESIGN AND METHODS - Self-measured, plasma-referenced glucose profiles and A1C values were evaluated fromparticipants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated. RESULTS - On prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8mmol/L), andmean A1C was 8.7%. BHG contributed an average of 76-80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32-41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64-71%. BHG contributions for patients with A1C averaging 7.6-7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively. CONCLUSIONS - When A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods. © 2011 by the American Diabetes Association.

Rosenstock J.,Dallas Diabetes and Endocrine Center | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Blevins T.C.,Texas Diabetes and Endocrinology | Morrow L.A.,Profil Institute for Clinical Research Inc. | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVEdTo compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGNANDMETHODSdIn this randomized, Phase 2, open-label, 232 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTSdLY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = 29.9 mg/dL [90% CI 214.6 to 25.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P,0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONSdIn type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reducedweight and lowered mealtime insulin doses. Copyright © 2013 by the American Diabetes Association.

Rosenstock J.,Dallas Diabetes and Endocrine Center
Expert Review of Endocrinology and Metabolism | Year: 2010

Saxagliptin (Onglyza™, Bristol-Myers Squibb, NJ, USA and AstraZeneca, DE, USA) is a potent, orally active, once-daily dipeptidyl peptidase-4 inhibitor that is indicated as an adjunct to diet and exercise alone, or in combination with metformin, a thiazolidinedione or a sulfonylurea to improve glycemic control in adults with Type 2 diabetes mellitus. By inhibiting dipeptidyl peptidase-4, saxagliptin increases concentrations of the intact forms of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, prolonging their effects. Saxagliptin also improves β-cell function, increases postprandial insulin secretion and reduces postprandial glucagon secretion. Saxagliptin is generally well tolerated with weight-neutral effects and a low incidence of hypoglycemia. Multicenter randomized trials have shown that saxagliptin as monotherapy, as initial therapy with metformin or as add-on therapy with metformin, a sulfonylurea or a thiazolidinedione leads to significant decreases in glycated hemoglobin levels, fasting and postprandial plasma glucose levels and higher percentages of patients attaining target glycated hemoglobin of less than 7% compared with controls. © 2010 Expert Reviews Ltd.

Rosenstock J.,Dallas Diabetes and Endocrine Center | Hansen L.,Bristol Myers Squibb | Zee P.,Bristol Myers Squibb | Li Y.,Astrazeneca | And 3 more authors.
Diabetes Care | Year: 2015

OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin. RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA1c ≥8.0% and ≤12.0% (64-108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET. RESULTS Patients had a mean baseline HbA1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m2. At week 24, the adjusted mean change from the baseline HbA1c was -1.5% (-16.1mmol/mol) with SAXA+DAPA+MET versus -0.9% (-9.6 mmol/mol) with SAXA+MET (difference 20.59% [-6.4 mmol/mol], P < 0.0001) and -1.2% (-13.1 mmol/mol) with DAPA+MET (difference 20.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in ≤1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia. CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to backgroundmetformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone. © 2015 by the American Diabetes Association.

Buse J.B.,University of North Carolina at Chapel Hill | DeFronzo R.A.,University of Texas Health Science Center at San Antonio | Rosenstock J.,Dallas Diabetes and Endocrine Center | Kim T.,Elcelyx Therapeutics | And 4 more authors.
Diabetes Care | Year: 2016

Delayed-release metformin (Met DR) is formulated to deliver the drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediaterelease metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. Research Design and Methods Study 1 was a phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblindedMet XR 1,000 or 2,000 mg (reference). Results The bioavailability of 1,000mg Met DR b.i.d. was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR q.d. produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/ Glucophage XR prescribing information. Conclusions Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action. © 2016 by the American Diabetes Association.

Buse J.B.,University of North Carolina at Chapel Hill | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Glass L.C.,Eli Lilly and Company | Heilmann C.R.,Eli Lilly and Company | And 4 more authors.
Annals of Internal Medicine | Year: 2011

Background: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1c (HbA1c) targets. Objective: To test whether twice-daily exenatide injections reduce HbA1c levels more than placebo in people receiving insulin glargine. Design: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1c level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) Setting: 59 centers in 5 countries. Patients: Adults with type 2 diabetes and an HbA1c level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). Intervention: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 μg twice daily, or placebo for 30 weeks. Measurements: The primary outcome was change in HbA1c level. Secondary outcomes included the percentage of participants with HbA1c values of 7.0% or less and 6.5% or less, 7-point selfmonitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. Results: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1c level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. Limitations: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1c levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. Conclusion: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. Primary Funding Source: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals. © 2011 American College of Physicians.

Gallwitz B.,University Hospital of Tuebingen | Rosenstock J.,Dallas Diabetes and Endocrine Center | Rauch T.,Boehringer Ingelheim | Bhattacharya S.,Boehringer Ingelheim | And 4 more authors.
The Lancet | Year: 2012

Background Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride). Methods In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A 1c (HbA 1c) 6·5-10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1-4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA 1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA 1c measurement, and had at least one on-treatment HbA 1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284. Findings 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA 1c (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (-0·16% [SE 0·03]) and glimepiride groups (-0·36% [0·03]; diff erence 0·20%, 97·5% CI 0·09-0·30), meeting the predefi ned non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with signifi cantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23-0·91, p=0·0213). Interpretation The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative eff ectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The fi ndings could improve decision making for clinical treatment when metformin alone is insuffi cient.

Rosenstock J.,Dallas Diabetes and Endocrine Center | Rigby S.P.,Summit Research Group | Ford D.M.,Daiichi Sankyo | Tao B.,Daiichi Sankyo | Chou H.S.,Daiichi Sankyo
Hormone and Metabolic Research | Year: 2014

Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥7.5% and ≤9.5%) with diet and exercise alone were randomized to receive colesevelam 3.75g/day (n=176) or placebo (n=181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (-2.92mmol/mol [0.3%]; p=0.01) and fasting plasma glucose (-10.3mg/dl; p=0.04) at week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (-11.2%; p<0.0001), total cholesterol (-5.1%; p=0.0005), non-high-density lipoprotein cholesterol (-7.4%; p=0.0001), and apolipoprotein B (-6.5%; p=0.0001) and increased apolipoprotein A-I (+2.4%; p=0.04), and triglycerides (+9.7%; p=0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved. ClinicalTrials.gov identifier: NCT00789737.© Georg Thieme Verlag KG Stuttgart. New York.

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