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Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Rodbard H.W.,Endocrine and Metabolic Consultants | Bain S.C.,University of Swansea | D'Alessio D.,University of Cincinnati | And 4 more authors.
Journal of Diabetes and its Complications | Year: 2013

Aim To investigate durability of efficacy and safety over 1 year of the sequence of liraglutide added to metformin followed by add-on insulin detemir if glycated hemoglobin (HbA1c) remains ≥ 7.0%. Methods Patients previously uncontrolled on metformin ± sulfonylurea with HbA1c ≥ 7.0% after 12 weeks of adding liraglutide 1.8 mg to metformin (run-in; sulfonylurea discontinued) were randomized 1:1 to 52 weeks' open-label add-on detemir (randomized treatment [RT] group; n = 162) or continuation without detemir (randomized control [RC] group; n = 161). Patients with HbA1c < 7.0% continued 52 weeks' unchanged treatment (observational group; n = 498). Results Run-in HbA1c improvement from 8.3% to 7.6% (-0.6%) was further enhanced in the RT group (-0.50%) and maintained in the RC group (+ 0.01%) over 52 weeks; estimated treatment difference (ETD)[95%CI]: - 0.51 [- 0.70;-0.31]; P < 0.0001. More RT (52%) than RC patients (22%) achieved HbA1c < 7.0% at 52 weeks (P < 0.0001). Run-in weight loss (-3.5 kg) was maintained in the RT (-0.05 kg) and enhanced in the RC group (- 1.02 kg) after 52 weeks; ETD [95%CI]: 0.97 [0.04;1.91]; P = 0.04. No major hypoglycemia occurred; minor hypoglycemia rates were low across groups (0.034-0.228 events/patient-year). Conclusions Supplementing metformin + liraglutide with detemir for 52 weeks improved glycemic control with sustained weight loss and low hypoglycemia rate. © 2013 the authors.


Rodbard H.W.,Endocrine and Metabolic Consultants | Gough S.,University of Oxford | Lane W.,Mountain Diabetes and Endocrine Center | Korsholm L.,Novo Nordisk AS | And 2 more authors.
Endocrine Practice | Year: 2014

Objective: This meta-analysis of 5 trials from the Phase 3a insulin degludec (IDeg) clinical trial program evaluated the risk of hypoglycemia in a subset of subjects with type 2 diabetes (T2D) who required high basal insulin doses at the end of the trials.Methods: This meta-analysis compared glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), basal insulin dose, body weight, and rates of overall and nocturnal confirmed hypoglycemia in a pooled population of T2D subjects using >60 U basal insulin at trial completion. Five Phase 3a, open-label, randomized, treat-to-target, confirmatory 26- or 52-week trials with IDeg (n = 2,262) versus insulin glargine (IGlar) (n = 1,110) administered once daily were included. Overall confirmed hypoglycemia was defined as self-measured blood glucose >56 mg/dL or any episode requiring assistance; nocturnal confirmed hypoglycemia had an onset between 00:01 and 05:59 AM.Results: More than one-third of IDeg- (35%) and IGlar- (34%) treated T2D subjects required >60 U of basal insulin daily at the ends of the trial. Patients achieved similar mean HbA1c values (estimated treatment difference [ETD] IDeg - IGlar: 0.05%, P = .44) while mean FPG values were lower with IDeg than IGlar (ETD: -5.9 mg/dL, P = .04) at end-of-trial. There was a 21% lower rate of overall confirmed hypoglycemic episodes for IDeg (estimated rate ratio [RR] IDeg/IGlar: 0.79, P = .02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes for IDeg (RR: 0.48, P<.01).Conclusion: In this post hoc meta-analysis, more than 30% of subjects with T2D required >60 U/day of basal insulin at the end of the trials. In these individuals, IDeg achieves similar HbA1c reduction with significantly less overall and nocturnal confirmed hypoglycemia compared with IGlar. Copyright © 2014 AACE.


Rodbard H.W.,Endocrine and Metabolic Consultants | Schnell O.,Helmholtz Center Munich | Unger J.,Catalina Research Institute | Rees C.,Hoffmann-La Roche | And 6 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - We evaluated the impact of an automated decision support tool (DST) on clinicians' ability to identify glycemic abnormalities in structured self-monitoring of blood glucose (SMBG) data and then make appropriate therapeutic changes based on the glycemic patterns observed. RESEARCH DESIGN AND METHODS - In this prospective, randomized, controlled, multicenter study, 288 clinicians (39.6% family practice physicians, 37.9% general internal medicine physicians, and 22.6% nurse practitioners) were randomized to structured SMBG alone (STG; n = 72); structured SMBG with DST (DST; n = 72); structured SMBG with an educational DVD (DVD; n = 72); and structured SMBG with DST and the educational DVD (DST+DVD; n = 72). Clinicians analyzed 30 patient cases (type 2 diabetes), identified the primary abnormality, and selected the most appropriate therapy. RESULTS - A total of 222 clinicians completed all 30 patient cases with no major protocol deviations. Significantly more DST, DVD, and DST+DVD clinicians correctly identified the glycemic abnormality and selected the most appropriate therapeutic option compared with STG clinicians: 49, 51, and 55%, respectively, vs. 33%(all P < 0.0001) with no significant differences among DST, DVD, and DST+DVD clinicians. CONCLUSIONS - Use of structured SMBG, combined with the DST, the educational DVD, or both, enhances clinicians' ability to correctly identify significant glycemic patterns and make appropriate therapeutic decisions to address those patterns. Structured testing interventions using either the educational DVD or the DST are equally effective in improving data interpretation and utilization. The DST provides a viable alternative when comprehensive education is not feasible, and it may be integrated into medical practices with minimal training. © 2012 by the American Diabetes Association.


Zinman B.,Samuel Lunenfeld Research Institute | Philis-Tsimikas A.,Scripps Whittier Diabetes Institute | Cariou B.,Nantes University Hospital Center | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patientswith type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS - In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS - In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS - Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. © 2012 by the American Diabetes Association.


Rodbard H.W.,Endocrine and Metabolic Consultants | Visco V.E.,DIM Clinica Privada | Andersen H.,Novo Nordisk AS | Hiort L.C.,Novo Nordisk AS | Shu D.H.W.,University of British Columbia
The Lancet Diabetes and Endocrinology | Year: 2014

Background: We compared stepwise addition of bolus insulin with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled on basal insulin plus oral antidiabetic drugs. Methods: The FullSTEP study was a phase 4, 32-week, randomised, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries to assess the effectiveness of a stepwise dosing approach versus a basal-bolus regimen. In this trial, 401 patients (mean age 59·8 years [SD 9·3]; HbA1c 7·9% [63 mmol/mol]; mean diabetes duration 12·6 years [SD 8·0]) were block randomised (ratio 1:1) to receive either stepwise treatment or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal throughout the trial. Patients in the stepwise group received one bolus dose with the largest meal, with additional insulin aspart doses before the next largest meal added to their regimen at 11 weeks and 22 weeks if HbA1c remained at 7% or higher. The primary outcome was non-inferiority of stepwise addition of bolus insulin versus complete basal-bolus therapy, as assessed by change in HbA1c from baseline to 32 weeks (non-inferiority margin of 0·4%). This trial is registered with ClinicalTrials.gov, number NCT01165684. Findings: The study was started on Oct 27, 2010, and completed on April 25, 2012. After 32 weeks, HbA1c change from baseline was -0·98% (95% CI -1·09 to -0·87) for the stepwise group and -1·12% (-1·23 to -1·00) for the basal-bolus group; mean treatment difference 0·14 (95% CI -0·02 to 0·30), non-significant (p=0·0876). Fewer hypoglycaemic episodes occurred in the stepwise group than in the basal-bolus group (rate ratio 0·58 [95% CI 0·45 to 0·75]; p<0·0001). Treatment-emergent adverse events did not differ between the two treatment groups. The most frequently reported treatment-emergent adverse event were nasopharyngitis, influenza, diarrhoea, headache, peripheral oedema, and wrong drug given. Three participants died: two before randomisation and one in the basal-bolus group (due to severe acute myocardial infarction and respiratory tract inflammation). Interpretation: Stepwise prandial insulin intensification provides glycaemic control non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycaemia risk and better patient satisfaction. Funding: Novo Nordisk. © 2014 Elsevier Ltd.


Gough S.C.L.,Churchill Hospital | Bode B.W.,Atlanta Diabetes Associates | Woo V.C.,University of Manitoba | Rodbard H.W.,Endocrine and Metabolic Consultants | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2015

Aims: To confirm, in a 26-week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. Methods: Insulin-naïve adults with type 2 diabetes randomized to once-daily IDegLira, insulin degludec or liraglutide, in addition to metformin±pioglitazone, continued their allocated treatment in this preplanned 26-week extension of the DUAL I trial. Results: A total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52weeks was reduced from baseline by 1.84% (20.2mmol/mol) for the IDegLira group, 1.40% (15.3mmol/mol) for the insulin degludec group and 1.21% (13.2mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7mmol/l) and insulin degludec (6.0mmol/l), but higher for liraglutide (7.3mmol/l). At 52weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, -2.80kg, p<0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira. Conclusions: These 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability. © 2015 John Wiley & Sons Ltd.


Rodbard H.W.,Endocrine and Metabolic Consultants | Cariou B.,Nantes University Hospital Center | Zinman B.,University of Toronto | Handelsman Y.,Metabolic Institute of America | And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Insulin degludec (IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. We compared once-daily IDeg and insulin glargine (IGlar), both in combination with metformin±dipeptidyl peptidase-4 inhibitors, in a 52-week, open-label, treat-to-target trial in patients with type 2 diabetes followed by a 52-week extension trial in which subjects [n=725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105weeks using the Short Form-36 (SF-36 v2) questionnaire. SF-36 scores were analysed (ITT population) using anova, with adjustments for covariates. At 105weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast (TC): 1.1 (0.1; 2.1)95%CI, p<0.05]. This was largely because of significantly better physical functioning [TC: 1.1 (0.0; 2.3)95%CI, p<0.05] and bodily pain sub-domain scores [TC: 1.5 (0.2; 2.9)95%CI, p<0.05]. Improvements in health status with IDeg compared to IGlar were maintained after 2years. © 2014 The Authors.


Rodbard H.W.,Endocrine and Metabolic Consultants | Cariou B.,Nantes University Hospital Center | Zinman B.,Samuel Lunenfeld Research Institute | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetic Medicine | Year: 2013

Aims: The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. Methods: This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. Results: At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). Conclusions: In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. © 2013 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.


Mathieu C.,Catholic University of Leuven | Rodbard H.W.,Endocrine and Metabolic Consultants | Cariou B.,Nantes University Hospital Center | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Aim: Two treatment strategies were compared in patients with type 2 diabetes (T2DM) on basal insulin requiring intensification: addition of once-daily (OD) liraglutide (Lira) or OD insulin aspart (IAsp) with largest meal. Methods: Subjects completing 104weeks (52-week main trial BEGIN ONCE-LONG + 52-week extension) on insulin degludec (IDeg) OD + metformin with HbA1c≥7.0% (≥53mmol/mol) were randomized to IDeg+Lira [n=88, mean HbA1c: 7.7% (61mmol/mol)] or IDeg+IAsp (n=89, mean HbA1c: 7.7%) for 26weeks, continuing metformin. Subjects completing 104weeks with HbA1c <7.0% continued IDeg+metformin in a third, non-randomized arm (n=236). Results: IDeg+Lira reduced HbA1c (-0.74%-points) significantly more than IDeg+IAsp (-0.39%-points); estimated treatment difference (ETD) (IDeg+Lira-IDeg+IAsp) -0.32%-points (95% CI -0.53; -0.12); p=0.0024. More IDeg+Lira (49.4%) than IDeg+IAsp (7.2%) subjects achieved HbA1c <7.0% without confirmed hypoglycaemia [plasma glucose <3.1mmol/l (<56mg/dl) or severe hypoglycaemia) and without weight gain; estimated odds ratio (IDeg+Lira/IDeg+IAsp) 13.79 (95% CI 5.24; 36.28); p<0.0001. IDeg+Lira subjects had significantly less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss (-2.8kg) versus IDeg+IAsp (+0.9kg); ETD (IDeg+Lira-IDeg+IAsp) -3.75kg (95% CI -4.70; -2.79); p<0.0001. Other than more gastrointestinal side effects with IDeg+Lira, no safety differences occurred. Durability of IDeg was established in the non-randomized arm, as mean HbA1c remained <7.0% [mean 6.5% (48mmol/mol) at end-of-trial]. Conclusions: IDeg+Lira improved long-term glycaemic control, with weight loss and less hypoglycaemia versus adding a single daily dose of IAsp in patients with T2DM inadequately controlled with IDeg+metformin. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.


Buse J.B.,University of North Carolina at Chapel Hill | Rodbard H.W.,Endocrine and Metabolic Consultants | Serrano C.T.,Hospital Of La Ribera | Luo J.,Eli Lilly and Company | And 5 more authors.
Diabetes Care | Year: 2016

To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patientswith type 2 diabetes (hemoglobin A1c [HbA1c]£9%[75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (20.82% [28.9 mmol/mol] vs. 20.29% [23.2 mmol/mol]; least squares mean difference 20.52%, 95%CI20.67 to20.38 [25.7mmol/mol, 95%CI27.3 to24.2; P < 0.001); greater reduction in HbA1cwith BIL wasmaintained at 52weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC. © 2016 by the American Diabetes Association.

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