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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. Source


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. Source


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. Source


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. Source


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. Source

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