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      Diurnal Glycemic Patterns during an 8-Week Open-Label Proof-of-Concept Trial of Empagliflozin in Type 1 Diabetes

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          Abstract

          Background

          We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM).

          Methods

          In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUC TOTAL 12:00am-11:55pm; AUC DAY 7:05am-10:55pm, AUC NIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL).

          Results

          The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m 2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUC TOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUC NIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUC DAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects.

          Conclusions

          We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime.

          Trial Registration

          Clinicaltrials.gov NCT01392560

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          Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes

          Julio Rosenstock, Naresh Aggarwal, David Polidori … (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.
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            Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy

            Julio Rosenstock, Marisa Vico, Li-li Wei … (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. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA1c change 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 HbA1c 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%) compared with 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 HbA1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk.
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              A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers

              John Wilding, Paul Norwood, Caroline T'joen … (2009)
              OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.
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                Author and article information

                Contributors
                Maciej Buchowski: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 6 November 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 11
                Electronic Location Identifier: e0141085
                Affiliations
                [1 ]Department of Medicine, Division of Endocrinology and Metabolism, University of Toronto, Toronto, ON, Canada
                [2 ]Department of Medicine, Division of Nephrology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
                [3 ]Boehringer Ingelheim Canada Ltd./Ltée, Burlington, ON, Canada
                [4 ]Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
                [5 ]WHO Collaborating Center, Minneapolis, Minnesota, United States of America
                [6 ]Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America
                [7 ]Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim, Germany
                [8 ]Boehringer Ingelheim Norway K.S, Asker, Norway
                Vanderbilt University, UNITED STATES
                Author notes

                Competing Interests: BAP has received speaker honoraria from Medtronic Inc., Johnson and Johnson, Roche, GlaxoSmithKline Canada, Novo Nordisk and Sanofi; has received research grant support from Medtronic and Boehringer Ingelheim; and serves as a consultant for Neurometrix. DZC has received speaker honoraria from Merck, Boehringer Ingelheim, Janssen, and research funding from Astellas Pharma and Boehringer Ingelheim. HP has received speaker honoraria from Janssen, Boehringer Ingelheim and AstraZeneca. BZ has received research support and or consulting honoraria from Boehringer Ingelheim, Janssen, AstraZeneca, Eli Lilly, Novo Nordisk, Merck and Sanofi. RM received research support from Boehringer Ingelheim and honoraria for speaking from Sanofi and Abbott Diabetes Care. None of the above awards or honoraria are directly associated with this specific study. JL and HT have no conflicts of interest to declare. NS, NF, SK, HJW, UCB and OEJ are employees of Boehringer Ingelheim. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: BAP DC NS NF SK HJW UCB OEJ. Performed the experiments: BAP DC JL HP HT BZ RM. Analyzed the data: BAP DC JL HP HT BZ RM NS NF SK HJW UCB OEJ. Wrote the paper: BAP DC JL HP HT BZ RM NS NF SK HJW UCB OEJ.

                Article
                Publisher ID: PONE-D-15-13450
                DOI: 10.1371/journal.pone.0141085
                PMC ID: 4636141
                PubMed ID: 26544192
                SO-VID: a5d6374d-52dd-4147-add8-9a928a0ccfba
                Copyright statement: Copyright @ 2015
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 29 May 2015
                Date accepted : 2 October 2015
                Page count
                Figures: 2, Tables: 1, Pages: 11
                Funding
                This study was funded by Boehringer Ingelheim and Eli Lilly. Boehringer Ingelheim’s involvement included study design, data collection and data analysis. Eli Lilly’s involvement was limited to co-funding of the study.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are included in the supplemental files.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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