research letter
Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0–≤9.5% (53–80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose–response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed. Keywords: glycaemic control, remogliflozin etabonate, SGLT2, type 2 diabetes Date submitted 3 July 2014; date of first decision 1 August 2014; date of final acceptance 11 September 2014
Introduction Type 2 diabetes is a complex metabolic disease that often requires multiple therapeutic interventions for effective treatment. Inhibition of sodium-dependent glucose transporter 2 (SGLT2) offers a new approach for the treatment of type 2 diabetes through increased renal glucose excretion, which results in decreased blood glucose and weight loss [1]. Several selective SGLT2 inhibitors are currently in development or have been approved for use [2]. Remogliflozin etabonate (RE) is a prodrug of the active moiety remogliflozin, and is a potent and selective O-glycoside inhibitor of SGLT2 [3]. The purpose of the present study was to determine the efficacy, safety and tolerability of once-daily RE as a monotherapy for 12 weeks, in drug-naïve people with type 2 diabetes.
Methods The study was approved by appropriate independent ethics committees and regulatory authorities, and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained before participation in the study. An independent data monitoring committee reviewed the conduct and unblinded data at ∼2-month intervals. In this double-blind randomized placebo- and activecontrolled, parallel group study, participants entered a 2-week screening period and were randomized to receive either RE 100, 250, 500 or 1000 mg once daily, RE 250 mg twice daily, matching placebo or pioglitazone 30 mg once daily for Correspondence to: William O. Wilkison PhD, Islet Sciences, Inc., 8601 Six Forks Road, Suite 400 Raleigh, NC 27615, USA. E-mail: [email protected]
12 weeks. Efficacy and safety assessments were performed at baseline, 4, 8 and 12 weeks. The treatment period was followed by a 2-week follow-up period. Individuals with either newly diagnosed or treatment-naïve type 2 diabetes were recruited to the study. The participants were aged 18–70 years, and had a glycated haemoglobin (HbA1c) concentration of 7.5–9.5% (58–80 mmol/mol) during screening; later adjustment to include participants with 7.0% HbA1c was required (up to a maximum of 20% of the population). Exclusions included those with a body mass index of ≤22 or ≥43 kg/m2 , an estimated glomerular filtration rate 100 mg once daily showed a significant trend (p < 0.047) in dose response for the mean change from baseline in HbA1c at week 12 (Table 1). The improvements were observed at week 4, and were sustained through to the last study assessment at week 12 (Figure S1). Clinically and statistically significant improvements in fasting plasma glucose concentrations, with changes from baseline at week 12 ranging from 0.85 to 1.06 mmol/l (Figure S2) were also observed. By contrast, decreases in HbA1c (0.19%) and fasting plasma glucose (0.51 mmol/l) concentrations with pioglitazone 30 mg once daily did not reach statistical significance in the present study. A non-dose-ordered and statistically significant decrease in body weight was observed in RE >100 mg treatment groups at week 12. Mean changes in weight ranged from 1.44 to 1.51 kg when compared with placebo (Figure S3). No significant changes from baseline were noted in total cholesterol, HDL cholesterol, LDL cholesterol, or triglyceride concentrations with once-daily dosing of RE (Table 2). Interestingly, however, an increase in LDL cholesterol was observed in the 250 mg RE twice-daily dose.
2 Sykes et al.
The rate of adverse events reported with RE was slightly higher (31–59% in the once-daily and 56% in the 250 mg twice-daily treatment groups) compared with the pioglitazone (34%) and placebo groups (22%). Overall the frequency of individual events was low (100 mg. Although it is difficult to make comparisons across different studies conducted in different patient populations, an improvement from baseline in HbA1c has been consistently observed by other SGLT2 inhibitors [1]. Treatment with SGLT2 inhibitors showed slight increases in HDL cholesterol and decreases in triglycerides [6,7]. Once-daily RE showed a similar pattern, although not in all groups. LDL cholesterol did not change in treatment groups
2014
research letter
DIABETES, OBESITY AND METABOLISM
Table 2. Summary of LDL cholesterol, HDL cholesterol, triglycerides, and LDL/HDL cholesterol ratios in the intent-to-treat population.
RE Placebo (n = 33) Triglycerides Model: adjusted % change from baseline Difference from placebo*, † (95% CI) Total cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) LDL cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) HDL cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) LDL/HDL cholesterol ratio Model adjusted change from baseline: mean (s.e.)‡ Difference from placebo (95% CI)
RE twice daily
Pioglitazone once daily
100 mg (n = 37)
250 mg (n = 33)
500 mg (n = 34)
1000 mg (n = 35)
250 mg (n = 35)
30 mg (n = 34)
0.6
−12.9
−8.3
−3.8
−6.9
−15.9
−1.7 (−16.1, 15.2)
−14.8 (−27. 9, 0.7)
−10.3 (−23.6, 5.3)
−5.9 (−20.0, 10.7)
−9.0 (−22.8, 7.4)
−17.7 (−30.0, −3.3)
−2.9
−2.8
2.3
0.1
4.6
0.2
−3.3 (−10.0, 4.0)
−3.2 (−10.3, 4.4)
1.8 (−5.4, 9.5)
−0.3 (−7.4, 7.3)
4.1 (−3.4, 12.2)
−0.3 (−7.3, 7.3)
−8.8
−1.4
3.9
0.0
9.6
4.9
−8.9 (−19.4, 3.0)
−1.5 (−13.1, 11.7)
3.7 (−8.2, 17.2)
−0.1 (−11.6, 12.9)
9.5 (−3.3, 23.8)
4.8 (−7.2, 18.3)
−0.3
1.1
5.3
4.1
2.3
6.8
1.7 (−4.4, 8.1)
3.1 (−3.5, 10.0)
7.4 (0.8, 14.3)
6.2 (−0.3, 13.1)
4.4 (−2.2, 11.3)
8.9 (2.3, 16.1)
−0.19 (0.12)
−0.06 (0.13)
−0.13 (0.12)
−0.07 (0.12)
0.10 (0.12)
−0.07 (0.12)
−0.25 (−0.58, 0.08)
−0.12 (−0.46, 0.22)
−0.19 (−0.52, 0.14)
−0.13 (−0.46, 0.20)
0.05 (−0.29, 0.38)
−0.13 (−0.46, 0.21)
2.3
0.5
0.1
−1.9
0.06 (0.12)
CI, confidence interval; RE, Remogliflozin etabonate; s.e., standard error. *Based on analysis of covariance (ANCOVA): log (week 12) − log (baseline) = log (baseline) + treatment. †Derived from geometric mean ratio to placebo. ‡Based on ANCOVA: change = baseline + treatment.
receiving once-daily doses of RE, but the twice-daily (250 mg) cohort showed a significant increase in LDL cholesterol, as did participants in the twice-daily dosing study [8]. Interestingly, increases in LDL cholesterol of 3.1–9.5% and 2.1–10.8% have been observed for dapagliflozin and canagliflozin, respectively [6,7]. In the present study, RE was well tolerated. There was a higher, non-dose-ordered, incidence of adverse events on treatment. A low incidence of genital fungal infection occurred in the RE treatment groups and appeared to be dose-related at the higher doses [8]. A major common factor contributing to the incidence of genital fungal infections and increases in LDL cholesterol is that twice-daily RE and the other SGLT2 inhibitors have significantly longer drug exposure in participants. By contrast, because of the 2-h half-life of remogliflozin, exposure in the once-daily RE groups is limited to 9–12 h [9]. This suggests that limiting overnight inhibition of SGLT2 may alleviate the increased incidence of genital fungal infections and/or elevation of LDL cholesterol concentration. In conclusion, the present study has shown that, when used as a once-daily monotherapy, RE was well tolerated, improved glycaemic control in patients with type 2 diabetes and did not promote an increase in LDL cholesterol.
2014
A. P. Sykes1 , G. L. Kemp1 , R. Dobbins2 , R. O’Connor-Semmes2 , S. R. Almond3 , W. O. Wilkison4 , S. Walker4 & L. Kler1 1 Metabolic Pathways and Cardiovascular, GlaxoSmithKline, Uxbridge, UK 2 Centre for Metabolic Research, GlaxoSmithKline, Research Triangle Park, NC, USA 3 Clinical Statistics, GlaxoSmithKline, Mississauga, Canada 4 Islet Sciences, Inc., Raleigh, NC, USA
Acknowledgements Investigators for this study: Dr N. Aggarwal, Dr A. Cheema, Dr M. Dufresne, Dr R. Goldenberg, Dr L. Pliamm, Dr C. Powell, Dr A. Wade (Canada); Dr A. Andresová (Czech Republic); Dr M. Past, Dr H. Tupits, Dr L. Viitas (Estonia); Dr K.M. Derwahl, Dr T. Drescher, Dr M. Kaiser, Dr C. Klein, Dr E. Kluessendorf-Mediger, Dr I. Maier-Bosse, Dr H-E. Sarnighausen, Dr M. Schumacher, Dr K. Steinbach, Dr M. Stern, Dr P. Unterberg, Dr P. Weisweiler, Dr K. Weyland (Germany); Dr E. Pagkalos (Greece); Dr G. Bantwal; Dr V. Deshmukh, Dr S. Reddy, Dr V. Seshiah, Dr H. Thacker (India); Dr N. Mickuviene, Dr V. Urbanavicius, Dr L. Valius, Dr E. Veranauskiene (Lithuania); Dr L. F. Flota-Cervera, Dr G.
doi:10.1111/dom.12393 3
research letter Morales-Franco, Dr L. Sauque-Reyna (Mexico); Dr P. Napora, Dr M. Zyczynska (Poland); Dr E. Franco Cotto, Dr E. A. Perez Vargas, Dr L. Rivera Colon, Dr L. Rodriguez-Carrasquillo, Dr N. Unger, Dr J. Vazquez-Tanus (Puerto Rico); Dr I. Ferariu, Dr I. S. Halmagyi, Dr M. Stamoran (Romania); Dr E. Kravets (Russia); Dr L. Burgess, Dr M. Siebert (South Africa); Dr M. V. Vlasenko (Ukraine); Dr A. Ahmed, Dr C. Belletieri, Dr E. Bretton, Dr R. Broker, Dr A. Burton, Dr L. Cruz, Dr R. Eagerton Jr., Dr E. Fuentes, Dr R. Garcia, Dr A. Lacour, Dr K. Lee, Dr B. Luna, Dr R.J. Miller Jr., Dr J.R. Mitchell, Dr A. Mora, Dr W. Nabours, Dr P. Norwood, Dr S. Ong, Dr P. Philander, Dr L.S. Phillips, Dr M. Raikhel, Dr K. Sall, Dr M. Samson, Dr J. D. Sandoval, Dr M. Schoenwalder, Dr S. Schwartz, Dr G. Serfer, Dr C. R. Sharpe, Dr G. Smith, Dr J. Tieman, Dr J. Urena, Dr P. Weissman, Dr J. Withers, Dr E. Wolfson, Dr B. Zamora (United States of America). Funding for this study was provided by GlaxoSmithKline (study KG2110375; NCT00495469).
Conflict of Interest A. P. S., G. L. K., R. D., R. O’C. S., S. R. A., W. W., S. W. and L. K. were employees and/or stockholders of GlaxoSmithKline at the time that the study was conducted. All listed authors meet the criteria for authorship set out by the International Committee for Medical Journal Editors. Authors participated either in the design of the study, interpretation of the data, drafting and critical review of the manuscript, and approval of the final version for publication.
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Mean change in glycated haemoglobin concentration from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population. Figure S2. Mean change in fasting plasma glucose concentrations from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population.
4 Sykes et al.
DIABETES, OBESITY AND METABOLISM
Figure S3. Mean change in body weight from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population. Table S1. Participant disposition (all participants). Table S2. Summary of demographic characteristics (intent-to-treat population). Table S3. Summary of most common (≥5% participants in any group) on-therapy adverse events by treatment (safety population).
References 1. Abdul-Ghani MA, Norton L, DeFronzo RA. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes. Curr Diab Rep 2012; 12: 230–238. 2. Good H. The Expansion of the SGLT-2 Inhibitor Market. Available from URL: http:// www.diabetesincontrol.com/articles/54-/15573-the-expansion-of-the-sglt-2-in hibitor-market. Accessed 24 October 2014. 3. Dobbins RL, O’Connor-Semmes R, Kapur A et al. Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes patients. Diabetes Obes Metab 2012; 14: 15–22. 4. Rigalleau V, Lasseur C, Perlemoine C et al. Estimation of glomerular filtration rate in diabetic subjects Cockcroft formula or Modification of Diet in Renal Disease study equation? Diabetes Care 2005; 28: 838–843. 5. Tukey JW, Ciminera JL, Heyse JF. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 1985; 41: 295–301. 6. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effects of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223–2233. 7. Stenlöf K, Cefalu WT, Kim K-A et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes inadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15: 372–382. 8. Sykes AP, O’Connor-Semmes R, Dobbins R et al. Randomized trial demonstrating efficacy and safety of twice daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab 2014; DOI: 10.1111/dom.12391. 9. Hussey EK, Kapur A, O’Connor-Semmes R et al. Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus. BMC Pharmacol Toxicol 2013; 14: 25.
2014
Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0–≤9.5% (53–80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose–response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed. Keywords: glycaemic control, remogliflozin etabonate, SGLT2, type 2 diabetes Date submitted 3 July 2014; date of first decision 1 August 2014; date of final acceptance 11 September 2014
Introduction Type 2 diabetes is a complex metabolic disease that often requires multiple therapeutic interventions for effective treatment. Inhibition of sodium-dependent glucose transporter 2 (SGLT2) offers a new approach for the treatment of type 2 diabetes through increased renal glucose excretion, which results in decreased blood glucose and weight loss [1]. Several selective SGLT2 inhibitors are currently in development or have been approved for use [2]. Remogliflozin etabonate (RE) is a prodrug of the active moiety remogliflozin, and is a potent and selective O-glycoside inhibitor of SGLT2 [3]. The purpose of the present study was to determine the efficacy, safety and tolerability of once-daily RE as a monotherapy for 12 weeks, in drug-naïve people with type 2 diabetes.
Methods The study was approved by appropriate independent ethics committees and regulatory authorities, and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained before participation in the study. An independent data monitoring committee reviewed the conduct and unblinded data at ∼2-month intervals. In this double-blind randomized placebo- and activecontrolled, parallel group study, participants entered a 2-week screening period and were randomized to receive either RE 100, 250, 500 or 1000 mg once daily, RE 250 mg twice daily, matching placebo or pioglitazone 30 mg once daily for Correspondence to: William O. Wilkison PhD, Islet Sciences, Inc., 8601 Six Forks Road, Suite 400 Raleigh, NC 27615, USA. E-mail: [email protected]
12 weeks. Efficacy and safety assessments were performed at baseline, 4, 8 and 12 weeks. The treatment period was followed by a 2-week follow-up period. Individuals with either newly diagnosed or treatment-naïve type 2 diabetes were recruited to the study. The participants were aged 18–70 years, and had a glycated haemoglobin (HbA1c) concentration of 7.5–9.5% (58–80 mmol/mol) during screening; later adjustment to include participants with 7.0% HbA1c was required (up to a maximum of 20% of the population). Exclusions included those with a body mass index of ≤22 or ≥43 kg/m2 , an estimated glomerular filtration rate 100 mg once daily showed a significant trend (p < 0.047) in dose response for the mean change from baseline in HbA1c at week 12 (Table 1). The improvements were observed at week 4, and were sustained through to the last study assessment at week 12 (Figure S1). Clinically and statistically significant improvements in fasting plasma glucose concentrations, with changes from baseline at week 12 ranging from 0.85 to 1.06 mmol/l (Figure S2) were also observed. By contrast, decreases in HbA1c (0.19%) and fasting plasma glucose (0.51 mmol/l) concentrations with pioglitazone 30 mg once daily did not reach statistical significance in the present study. A non-dose-ordered and statistically significant decrease in body weight was observed in RE >100 mg treatment groups at week 12. Mean changes in weight ranged from 1.44 to 1.51 kg when compared with placebo (Figure S3). No significant changes from baseline were noted in total cholesterol, HDL cholesterol, LDL cholesterol, or triglyceride concentrations with once-daily dosing of RE (Table 2). Interestingly, however, an increase in LDL cholesterol was observed in the 250 mg RE twice-daily dose.
2 Sykes et al.
The rate of adverse events reported with RE was slightly higher (31–59% in the once-daily and 56% in the 250 mg twice-daily treatment groups) compared with the pioglitazone (34%) and placebo groups (22%). Overall the frequency of individual events was low (100 mg. Although it is difficult to make comparisons across different studies conducted in different patient populations, an improvement from baseline in HbA1c has been consistently observed by other SGLT2 inhibitors [1]. Treatment with SGLT2 inhibitors showed slight increases in HDL cholesterol and decreases in triglycerides [6,7]. Once-daily RE showed a similar pattern, although not in all groups. LDL cholesterol did not change in treatment groups
2014
research letter
DIABETES, OBESITY AND METABOLISM
Table 2. Summary of LDL cholesterol, HDL cholesterol, triglycerides, and LDL/HDL cholesterol ratios in the intent-to-treat population.
RE Placebo (n = 33) Triglycerides Model: adjusted % change from baseline Difference from placebo*, † (95% CI) Total cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) LDL cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) HDL cholesterol Model: adjusted % change from baseline Difference from placebo*, † (95% CI) LDL/HDL cholesterol ratio Model adjusted change from baseline: mean (s.e.)‡ Difference from placebo (95% CI)
RE twice daily
Pioglitazone once daily
100 mg (n = 37)
250 mg (n = 33)
500 mg (n = 34)
1000 mg (n = 35)
250 mg (n = 35)
30 mg (n = 34)
0.6
−12.9
−8.3
−3.8
−6.9
−15.9
−1.7 (−16.1, 15.2)
−14.8 (−27. 9, 0.7)
−10.3 (−23.6, 5.3)
−5.9 (−20.0, 10.7)
−9.0 (−22.8, 7.4)
−17.7 (−30.0, −3.3)
−2.9
−2.8
2.3
0.1
4.6
0.2
−3.3 (−10.0, 4.0)
−3.2 (−10.3, 4.4)
1.8 (−5.4, 9.5)
−0.3 (−7.4, 7.3)
4.1 (−3.4, 12.2)
−0.3 (−7.3, 7.3)
−8.8
−1.4
3.9
0.0
9.6
4.9
−8.9 (−19.4, 3.0)
−1.5 (−13.1, 11.7)
3.7 (−8.2, 17.2)
−0.1 (−11.6, 12.9)
9.5 (−3.3, 23.8)
4.8 (−7.2, 18.3)
−0.3
1.1
5.3
4.1
2.3
6.8
1.7 (−4.4, 8.1)
3.1 (−3.5, 10.0)
7.4 (0.8, 14.3)
6.2 (−0.3, 13.1)
4.4 (−2.2, 11.3)
8.9 (2.3, 16.1)
−0.19 (0.12)
−0.06 (0.13)
−0.13 (0.12)
−0.07 (0.12)
0.10 (0.12)
−0.07 (0.12)
−0.25 (−0.58, 0.08)
−0.12 (−0.46, 0.22)
−0.19 (−0.52, 0.14)
−0.13 (−0.46, 0.20)
0.05 (−0.29, 0.38)
−0.13 (−0.46, 0.21)
2.3
0.5
0.1
−1.9
0.06 (0.12)
CI, confidence interval; RE, Remogliflozin etabonate; s.e., standard error. *Based on analysis of covariance (ANCOVA): log (week 12) − log (baseline) = log (baseline) + treatment. †Derived from geometric mean ratio to placebo. ‡Based on ANCOVA: change = baseline + treatment.
receiving once-daily doses of RE, but the twice-daily (250 mg) cohort showed a significant increase in LDL cholesterol, as did participants in the twice-daily dosing study [8]. Interestingly, increases in LDL cholesterol of 3.1–9.5% and 2.1–10.8% have been observed for dapagliflozin and canagliflozin, respectively [6,7]. In the present study, RE was well tolerated. There was a higher, non-dose-ordered, incidence of adverse events on treatment. A low incidence of genital fungal infection occurred in the RE treatment groups and appeared to be dose-related at the higher doses [8]. A major common factor contributing to the incidence of genital fungal infections and increases in LDL cholesterol is that twice-daily RE and the other SGLT2 inhibitors have significantly longer drug exposure in participants. By contrast, because of the 2-h half-life of remogliflozin, exposure in the once-daily RE groups is limited to 9–12 h [9]. This suggests that limiting overnight inhibition of SGLT2 may alleviate the increased incidence of genital fungal infections and/or elevation of LDL cholesterol concentration. In conclusion, the present study has shown that, when used as a once-daily monotherapy, RE was well tolerated, improved glycaemic control in patients with type 2 diabetes and did not promote an increase in LDL cholesterol.
2014
A. P. Sykes1 , G. L. Kemp1 , R. Dobbins2 , R. O’Connor-Semmes2 , S. R. Almond3 , W. O. Wilkison4 , S. Walker4 & L. Kler1 1 Metabolic Pathways and Cardiovascular, GlaxoSmithKline, Uxbridge, UK 2 Centre for Metabolic Research, GlaxoSmithKline, Research Triangle Park, NC, USA 3 Clinical Statistics, GlaxoSmithKline, Mississauga, Canada 4 Islet Sciences, Inc., Raleigh, NC, USA
Acknowledgements Investigators for this study: Dr N. Aggarwal, Dr A. Cheema, Dr M. Dufresne, Dr R. Goldenberg, Dr L. Pliamm, Dr C. Powell, Dr A. Wade (Canada); Dr A. Andresová (Czech Republic); Dr M. Past, Dr H. Tupits, Dr L. Viitas (Estonia); Dr K.M. Derwahl, Dr T. Drescher, Dr M. Kaiser, Dr C. Klein, Dr E. Kluessendorf-Mediger, Dr I. Maier-Bosse, Dr H-E. Sarnighausen, Dr M. Schumacher, Dr K. Steinbach, Dr M. Stern, Dr P. Unterberg, Dr P. Weisweiler, Dr K. Weyland (Germany); Dr E. Pagkalos (Greece); Dr G. Bantwal; Dr V. Deshmukh, Dr S. Reddy, Dr V. Seshiah, Dr H. Thacker (India); Dr N. Mickuviene, Dr V. Urbanavicius, Dr L. Valius, Dr E. Veranauskiene (Lithuania); Dr L. F. Flota-Cervera, Dr G.
doi:10.1111/dom.12393 3
research letter Morales-Franco, Dr L. Sauque-Reyna (Mexico); Dr P. Napora, Dr M. Zyczynska (Poland); Dr E. Franco Cotto, Dr E. A. Perez Vargas, Dr L. Rivera Colon, Dr L. Rodriguez-Carrasquillo, Dr N. Unger, Dr J. Vazquez-Tanus (Puerto Rico); Dr I. Ferariu, Dr I. S. Halmagyi, Dr M. Stamoran (Romania); Dr E. Kravets (Russia); Dr L. Burgess, Dr M. Siebert (South Africa); Dr M. V. Vlasenko (Ukraine); Dr A. Ahmed, Dr C. Belletieri, Dr E. Bretton, Dr R. Broker, Dr A. Burton, Dr L. Cruz, Dr R. Eagerton Jr., Dr E. Fuentes, Dr R. Garcia, Dr A. Lacour, Dr K. Lee, Dr B. Luna, Dr R.J. Miller Jr., Dr J.R. Mitchell, Dr A. Mora, Dr W. Nabours, Dr P. Norwood, Dr S. Ong, Dr P. Philander, Dr L.S. Phillips, Dr M. Raikhel, Dr K. Sall, Dr M. Samson, Dr J. D. Sandoval, Dr M. Schoenwalder, Dr S. Schwartz, Dr G. Serfer, Dr C. R. Sharpe, Dr G. Smith, Dr J. Tieman, Dr J. Urena, Dr P. Weissman, Dr J. Withers, Dr E. Wolfson, Dr B. Zamora (United States of America). Funding for this study was provided by GlaxoSmithKline (study KG2110375; NCT00495469).
Conflict of Interest A. P. S., G. L. K., R. D., R. O’C. S., S. R. A., W. W., S. W. and L. K. were employees and/or stockholders of GlaxoSmithKline at the time that the study was conducted. All listed authors meet the criteria for authorship set out by the International Committee for Medical Journal Editors. Authors participated either in the design of the study, interpretation of the data, drafting and critical review of the manuscript, and approval of the final version for publication.
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Mean change in glycated haemoglobin concentration from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population. Figure S2. Mean change in fasting plasma glucose concentrations from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population.
4 Sykes et al.
DIABETES, OBESITY AND METABOLISM
Figure S3. Mean change in body weight from baseline (±standard error) for each visit (LOCF) in the intent-to-treat population. Table S1. Participant disposition (all participants). Table S2. Summary of demographic characteristics (intent-to-treat population). Table S3. Summary of most common (≥5% participants in any group) on-therapy adverse events by treatment (safety population).
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