Corresponding author: Dr Stuart Ross, LMC Endocrinology Centres, 102-5940 Macleod Trail SW, Calgary, Alberta, Canada
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Abstract Patients with T2DM with HbA1c ≥7% and ≤10% were randomized to receive empagliflozin 12.5 mg twice daily (bid) (n=219), 25 mg once daily (qd) (n=218), 5 mg bid (n=219) or 10 mg qd (n=220), or placebo (n=107) as add-on to stable dose metformin immediate release (IR) bid for 16 weeks. The primary endpoint was change from baseline in HbA1c at week 16. At week 16, change from baseline in HbA1c with empagliflozin bid was non-inferior to empagliflozin qd and vice versa. Adjusted mean (95% CI) difference in change from baseline in HbA1c with empagliflozin 12.5 mg bid versus 25 mg qd was -0.11% (-0.26, 0.03), and with empagliflozin 5 mg bid versus 10 mg qd was -0.02% (-0.16, 0.13). All empagliflozin regimens were well tolerated. Thus when used as add-on to metformin IR in patients with T2DM, the therapeutic effect of empagliflozin bid and qd regimens can be considered equivalent. Keywords: empagliflozin, glycaemic control, metformin, once daily, twice daily
Introduction Metformin is the recommended first-line pharmacological treatment for patients with type 2 diabetes (T2DM) . However, as T2DM progresses, addition of a second agent is often required to maintain glycemic control [1-3]. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption and so increases glucosuria, reducing hyperglycemia in patients with T2DM . Metformin reduces blood glucose principally by reducing hepatic gluconeogenesis . These complementary mechanisms of action, and the benefits seen when empagliflozin is added to metformin in patients with T2DM [6-8] suggest that a fixed dose combination (FDC) of empagliflozin and metformin may offer additional glucose control and weight loss, with a low risk of hypoglycemia. As metformin immediate release (IR) is administered twice daily (bid), an FDC of empagliflozin and metformin IR would require bid administration of empagliflozin. In healthy volunteers, no relevant pharmacokinetic or pharmacodynamic differences are observed between bid and qd empagliflozin regimens . Methods This study compared the efficacy and safety of bid regimens of empagliflozin 25 mg and 10 mg with qd regimens as add-on to metformin IR bid in patients with T2DM. Adults with T2DM with BMI ≤45 kg/m2 and HbA1c ≥7% and ≤10% at screening despite a diet and exercise regimen and treatment with a stable dose of metformin IR (≥1500 mg/day) for ≥12 weeks prior to randomization were eligible to participate. Key exclusion criteria are provided in the Supplementary Appendix. Following a 2-week placebo run-in, patients were randomized 2:2:2:2:1 to receive empagliflozin 12.5 mg bid, 25 mg qd, 5 mg bid, 10 mg qd, or placebo for 16 weeks. Randomization was stratified by region (Europe, North America, Latin America) and by HbA1c (<8.5% and ≥8.5%) and eGFR (≤60–89 ml/min/1.73m2 and ≥90 ml/min/1.73m2) at screening. Patients continued to receive metformin IR. Visits were scheduled at baseline and at weeks 4, 10 and 16 of treatment. Patients were followed up within 7 days of last study drug intake.Rescue medication could be initiated if, after an
overnight fast, a patient had a plasma glucose level >13.3 mmol/l, confirmed by a measurement on a different day. Use of other SGLT2 inhibitors or increasing the dose of metformin was not permitted. The study was registered with the EU Clinical Trials Register (eudract number 2012000905-53), carried out in compliance with the principles of the Declaration of Helsinki, in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice, and approved by relevant Institutional Review Boards and Independent Ethics Committees. The primary endpoint was change from baseline in HbA1c at week 16. The secondary endpoint was change from baseline in FPG at week 16. Exploratory endpoints included the proportion of patients with HbA1c ≥7% at baseline who had HbA1c <7% at week 16 and changes from baseline in weight, systolic BP (SBP) and diastolic BP (DBP) at week 16. Adverse events (AEs) reported during the study and up to 7 days after the last dose of study drug were coded using the Medical Dictionary for Drug Regulatory Activities [MedDRA]). Confirmed hypoglycaemic AEs were defined as AEs with plasma glucose ≤3.9 mmol/l and/or requiring assistance. Events consistent with urinary tract infection (UTI), genital infection, increased urination and volume depletion were identified using search categories based on 76, 87, 3 and 8 MedDRA preferred terms, respectively. Statistical analyses are described in the Supplementary Appendix. Briefly, the primary analysis was a test of non-inferiority of empagliflozin 12.5 mg bid versus 25 mg qd, and a test of non-inferiority of empagliflozin 5 mg bid versus 10 mg qd, in change from baseline in HbA1c at week 16, using a non-inferiority margin of 0.35%. The analysis was undertaken in patients who received ≥1 dose of study drug and had a baseline and on-treatment HbA1c value. Values observed after a patient started rescue therapy were set to missing and imputed using a last observation carried forward approach. A post-hoc analysis evaluating non-inferiority of empagliflozin qd regimens to bid regimens was conducted using the same model as the primary analysis. Superiority of empagliflozin doses versus placebo was tested
to demonstrate assay sensitivity. Safety was assessed in patients who received ≥1 dose of study drug. Results In total, 983 patients were treated with empagliflozin 12.5 mg bid (n = 219), empagliflozin 25 mg qd (n = 218), empagliflozin 5 mg bid (n = 219), empagliflozin 10 mg qd (n = 220) or placebo (n = 107). On-treatment HbA1c values were not available for 18 patients (figure S1, Supporting Information). Baseline characteristics were balanced across treatment groups (Table S1). Non-inferiority was demonstrated for change from baseline in HbA1c at week 16 for empagliflozin bid versus qd regimens; adjusted mean (95% CI) differences in change from baseline were -0.11% (-0.26, 0.03) for empagliflozin 12.5 mg bid versus empagliflozin 25 mg qd, and -0.02% (-0.16, 0.13) for empagliflozin 5 mg bid versus empagliflozin 10 mg qd (both p < 0.001) (Table 1, figure 1). Non-inferiority was also demonstrated for change from baseline in HbA1c at week 16 for empagliflozin qd versus bid regimens (Table 1, figure 1). Compared with placebo, reductions in HbA1c at week 16 were greater with every empagliflozin regimen and a higher proportion of patients achieved HbA1c <7% (all p < 0.05) (Table 1). The results of sensitivity analyses were consistent with the primary analysis (Table S2, figure S2). Reductions from baseline in FPG, weight and SBP were significantly greater with every empagliflozin regimen versus placebo (Table 1). Reductions from baseline in DBP were significantly different versus placebo for empagliflozin 12.5 mg bid, 25 mg qd and 5 mg bid (Table 1). Changes in pulse rate were similar across groups (see Supplementary Appendix). The proportions of patients with ≥1 AE were similar in all groups (Table S3). Almost all AEs were mild or moderate in intensity. There were few serious AEs and no deaths. Confirmed hypoglycaemic AEs were reported in 1 patient in every group, except the empagliflozin 12.5 mg bid group (none); no events required assistance. Events consistent with increased urination were reported in 2.7%, 2.8%, 2.7%, 2.3% and 1.9% of patients
treated with empagliflozin 12.5 mg bid, 25 mg qd, 5 mg bid and 10 mg qd and placebo, respectively; there was no difference in nocturia across groups (Table S3). Events consistent with volume depletion were reported in 1 patient on empagliflozin 12.5 mg bid and 2 patients on empagliflozin 10 mg qd only (Table S3). Events consistent with UTI and genital infection and changes in laboratory measurements are described in the Supplementary Appendix and Table S4, respectively. Conclusions This study demonstrated that when given as add-on to metformin IR bid in patients with T2DM, qd and bid regimens of empagliflozin 10 mg and 25 mg showed therapeutic equivalence in reducing HbA1c after 16 weeks’ treatment. Empagliflozin bid and qd regimens appeared to reduce HbA1c, FPG, weight, and SBP versus placebo to a similar extent. All empagliflozin regimens were well tolerated. Confirmed hypoglycaemic AEs were rare in all treatment groups. Importantly, there was no increase in nocturia with empagliflozin. In conclusion, the therapeutic effect of empagliflozin bid and qd regimens can be considered equivalent. This demonstrates the potential for empagliflozin to be given as an FDC with metformin IR as second line therapy.
Acknowledgements This study was funded by Boehringer Ingelheim and Eli Lilly and Company. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Clare Ryles and Wendy Morris of Fleishman-Hillard Group, Ltd during the preparation of this research letter. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development and have approved the final version.
Declaration of interests SR has received honoraria and/or research grants from Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Janssen, and Merck. CT, JC, TM, HJW and UCB are all employees of Boehringer Ingelheim.
Contributor statements SR contributed to the acquisition and interpretation of data and writing of the letter. CT, JC, TM and UCB contributed to the study design, interpretation of data and writing of the letter. HJW contributed to the interpretation of data and reviewed/edited the letter.
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Figure Legend Figure 1. Non-infe eriority testss for empagliflozin bid versus v qd re egimens and qd versuss bid ns in change from base eline in HbA A1c at weekk 16 (analyssis of covariance [ANC COVA] regimen model, last observation carrie ed forward [L LOCF] in pa atients who received ≥1 dose of study drug an nd had a baseline and o on-treatmen nt HbA1c va alue).
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