Dallas Diabetes and Endocrine Center at Medical City

Dallas, TX, United States

Dallas Diabetes and Endocrine Center at Medical City

Dallas, TX, United States

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Ratner R.E.,MedStar Research Institute | Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Boka G.,Sanofi S.A.
Diabetic Medicine | Year: 2010

Aims To evaluate the dose-response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes. Methods Randomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) ≥ 7.0 and < 9.0% (≥ 53 and < 75 mmol/mol)] on metformin (≥ 1000 mg/day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 μg once daily or twice daily or placebo. The primary end-point was change in HbA1c from baseline to 13 weeks in the intent-to-treat population. Results Lixisenatide significantly improved mean HbA1c from a baseline of 7.55% (59.0 mmol/mol); respective mean reductions for 5, 10, 20 and 30 μg doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol/mol), on once-daily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol/mol) on twice-daily administrations vs. 0.18% (2.0 mmol/mol) with placebo (all P < 0.01 vs. placebo). Target HbA1c < 7.0% (53 mmol/mol) at study end was achieved in 68% of patients receiving 20 and 30 μg once-daily lixisenatide vs. 32% receiving placebo (P < 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from -2.0 to -3.9 kg with lixisenatide vs. -1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea. Conclusions Lixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose-response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 μg once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, once-daily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies. © 2010 Diabetes UK.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Raccah D.,University Hospital Sainte Marguerite | Koranyi L.,DRC Ltd | Maffei L.,Investigacion Clinica Aplicada | And 3 more authors.
Diabetes Care | Year: 2013

OBJECTIVE To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODSdAdults with diabetes inadequately controlled (HbA1c 7-10%) with metformin were randomized to lixisenatide 20 mg once daily (n = 318) or exenatide 10 mg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA1c change from baseline to week 24. RESULTSdLixisenatide once daily demonstrated noninferiority in HbA1c reduction versus exenatide twice daily. The least squares mean change was 20.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus 20.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033-0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA1c,7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P , 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P , 0.05). CONCLUSIONSdAdd-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily. © 2013 by the American Diabetes Association.


Riddle M.C.,Oregon Health And Science University | Forst T.,Institute for Clinical Research and Development | Aronson R.,LMC Diabetes & Endocrinology | Sauque-Reyna L.,Institute Diabetes Obesidad y Nutricion Sociedad Civil | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial.We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. RESEARCH DESIGN AND METHODS-This double-blind, parallel-group trial enrolled patients with HbA1c 7-10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA 1c 7-9% were randomized to lixisenatide 20 μg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA 1c change after randomization. RESULTS-The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m2, and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, -0.32%; 95% CI, -0.46 to -0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo -3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo -0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide. CONCLUSIONS-Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin. © 2013 by the American Diabetes Association.


Schernthaner G.,Rudolfstiftung Hospital Vienna | Gross J.L.,Federal University of Rio Grande do Sul | Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Guarisco M.,Stanocola Medical Clinic | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS-In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports. RESULTS-At 52 weeks, canagliflozin 300mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mgin reducing A1C(-1.03%[-11.3mmol/mol] and -0.66% [-7.2 mmol/mol], respectively; least squares mean difference between groups, -0.37% [95% CI, -0.50 to -0.25] or -4.0 mmol/mol [-5.5 to -2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis-related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups. CONCLUSIONS-Findings suggest that canagliflozinmay be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea. © 2013 by the American Diabetes Association.


Riddle M.C.,Oregon Health And Science University | Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Vlajnic A.,SanofiUS Inc. | Gao L.,Analysta
Diabetes, Obesity and Metabolism | Year: 2014

Aim: Many patients with type 2 diabetes mellitus (T2DM) initiate insulin therapy when other treatments fail; how best to do this is poorly defined. Methods: People with T2DM [n=588; glycated haemoglobin A1C (A1C) >7.0%, mean baseline 9.4%] were randomized to twice-daily premixed protamine-aspart/aspart insulin (PM-2), once-daily insulin glargine plus zero to one prandial insulin glulisine injection (G+1), or insulin glargine plus zero to three prandial injections (G+3). Insulin was titrated for 60weeks. Efficacy and safety outcomes were assessed. Results: Discontinuation rates were 53 of the 194 (27%), 44 of the 194 (23%) and 38 of the 194 (20%), for PM-2, G+1 and G+3. Glycaemic control improved in all groups (A1C 7.2±1.37, 7.1±1.68 and 7.0±1.21% at 60weeks; 7.5±1.29, 7.2±1.62 and 7.2±1.63% at endpoint). G+1 was statistically non-inferior to PM-2 in reducing A1C. G+3 was slightly superior to PM-2 in attaining <7.0% at 60weeks, but only when the analysis included Good Clinical Practice non-adherent sites. Hypoglycaemia with plasma glucose <2.8mmol/l was more frequent with PM-2 versus G+1 and G+3; [adjusted incidence: 46 (p=0.0087) vs. 33 (p=0.0045) and 31.5%; events per patient-year: 1.9 vs. 0.8 and 0.9, p≤0.0001]. Insulin dosage and weight-gain were similar. Conclusion: Basal insulin plus a single prandial injection is as effective in improving glycaemic control as premixed insulin. Full basal-prandial therapy is only slightly more effective than premixed insulin. Stepwise basal-prandial regimens improve glycaemic control with less hypoglycaemia than twice-daily premixed insulin. © 2013 John Wiley & Sons Ltd.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Aggarwal N.,Aggarwal and Associates Ltd. | Polidori D.,Janssen Global Services LLC | Zhao Y.,Janssen Global Services LLC | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS - This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS - Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS - Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females. © 2012 by the American Diabetes Association.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Vico M.,Institute Investigaciones Clinicas Zarate | Wei L.,Bristol Myers Squibb | Salsali A.,Bristol Myers Squibb | List J.F.,Bristol Myers Squibb
Diabetes Care | Year: 2012

OBJECTIVE - To examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone. RESEARCH DESIGN AND METHODS - Treatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. Theywere then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA 1cchange from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis. RESULTS - At week 24, the mean reduction from baseline in HbA 1c was -0.42% for placebo versus -0.82 and -0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7-1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6-9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0-8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1-4.3%) comparedwith placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare. CONCLUSIONS - In patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA 1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk. © 2012 by the American Diabetes Association.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Jelaska A.,Boehringer Ingelheim Pharmaceuticals | Frappin G.,Boehringer Ingelheim | Salsali A.,Boehringer Ingelheim Pharmaceuticals | And 3 more authors.
Diabetes Care | Year: 2014

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/m 2; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25mg (n = 189), or placebo ( n = 188) for 52 weeks. Insulin dosewas 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 frombaseline 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. © 2014 by the American Diabetes Association.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | Year: 2010

To evaluate the efficacy and safety of initial combination therapy with metformin plus colesevelam in patients with early type 2 diabetes. In this 16-week, randomized, double-blind, placebo-controlled study, adults with type 2 diabetes (hemoglobin A1c [A1C] values of 6.5% to 10.0%) and hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] levels > or =100 mg/dL) were randomly assigned (1:1) to colesevelam (3.75 g/d) or placebo in combination with open-label metformin (850 mg/d; uptitrated at week 2 to 1,700 mg/d). The primary efficacy evaluation was change in A1C from baseline to study end (week 16 with last observation carried forward). In total, 286 patients were randomized: metformin/colesevelam (n = 145) or metformin/placebo (n = 141). Mean A1C was reduced by 1.1% with metformin/colesevelam (from 7.8% at baseline to 6.6% at study end) and by 0.8% with metformin/placebo (from 7.5% to 6.7%), resulting in a treatment difference of -0.3% at study end (P = .0035). In addition, metformin/colesevelam significantly reduced LDL-C (-16.3%), total cholesterol (-6.1%), non-high-density lipoprotein cholesterol (-8.3%), apolipoprotein B (-8.0%), and high-sensitivity C-reactive protein (-17%) and increased apolipoprotein A-I (+4.4%) and triglycerides (+18.6%) versus metformin/placebo (P<.01 for all). The proportions of patients who achieved recommended goals with metformin/colesevelam versus metformin/placebo, respectively, were as follows: A1C <7.0% (67% versus 56% [P = .0092]), LDL-C <100 mg/dL (48% versus 18% [P<.0001]), and composite A1C <7.0% + LDL-C <100 mg/dL (40% versus 12% [P<.0001]). Safety and tolerability were similar between the treatment groups. Metformin plus colesevelam may be a valid option for initial therapy to achieve glycemic and lipid goals safely in early type 2 diabetes.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Wilson C.,Takeda Global Research and Development Center Inc. | Fleck P.,Takeda Global Research and Development Center Inc.
Diabetes, Obesity and Metabolism | Year: 2013

Aim: To prospectively evaluate the efficacy and safety of alogliptin versus glipizide in elderly patients with type 2 diabetes mellitus (T2DM) over 1year of treatment. Methods: This was a randomized, double-blind, active-controlled study of elderly T2DM patients (aged 65-90years) with mild hyperglycaemia on diet/exercise therapy alone [glycosylated haemoglobin (HbA1c) 6.5-9.0%] or plus oral antidiabetic monotherapy (HbA1c 6.5-8.0%). Patients were randomized to once-daily alogliptin 25mg or glipizide 5mg titrated to 10mg, if needed. Hypoglycaemic episodes were systematically captured under predefined criteria. Results: In the primary analysis, HbA1c mean changes from a baseline of 7.5% were -0.14% with alogliptin (n=222) and -0.09% with glipizide (n=219) at the end of the study, demonstrating non-inferiority of alogliptin to glipizide [least squares (LS) mean difference=-0.05%; one-sided 97.5% confidence interval (CI): -∞, 0.13%]. More clinically relevant HbA1c reductions occurred among patients who completed the study: -0.42 and -0.33% with alogliptin and glipizide, with non-inferiority again confirmed (LS mean difference=-0.09%; one-sided 97.5% CI: -∞, 0.07%). Overall, alogliptin was safe and well tolerated, with notably fewer hypoglycaemic episodes than glipizide [5.4% (31 episodes) vs. 26.0% (232 episodes), respectively]; three patients experienced severe hypoglycaemia, all with glipizide. Alogliptin also resulted in favourable weight changes versus glipizide (-0.62 vs. 0.60kg at week 52; p<0.001). Conclusions: Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1year of treatment, with substantially lower risk of hypoglycaemia and without weight gain. © 2013 John Wiley & Sons Ltd.

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