original article
Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin N. B. Amin1 , X. Wang1,∗ , S. M. Jain2 , D. S. Lee1 , G. Nucci1 & J. M. Rusnak1 1 Pfizer Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA 2 TOTALL Diabetes Hormone Institute, Indore, India
Aim: To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored. Results: Ertugliflozin (1–25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) −0.45% (1 mg) to −0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (−0.76%; p = 0.0001)], FPG (LSM −1.17 to −1.90 mmol/l; p < 0.0001) and body weight (−1.15 to −2.15%; p < 0.0001). The LSM SBP decreased by −3.4 to −4.0 mmHg from baseline with ertugliflozin 5–25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo. Conclusion: Ertugliflozin (1–25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated. Keywords: ertugliflozin, HbA1c, PF-04971729, sodium-glucose linked co-transporter (SGLT), type 2 diabetes mellitus (T2DM) Date submitted 12 December 2014; date of first decision 6 January 2015; date of final acceptance 3 March 2015
Introduction In 2013, an estimated 382 million people had diabetes [1] and the World Health Organization predicts that, by 2030, diabetes will be the seventh leading cause of death [2]. Metformin is a recommended first-line therapy for type 2 diabetes (T2DM) [3,4], but the progressive nature of diabetes frequently necessitates more intensive, or combination treatment regimens to reach and/or maintain glycaemic control [4] and to reduce the risk factors for cardiovascular complications [5–7]. In the maintenance of glucose homeostasis by the kidney [8,9], glucose filtered at the glomerulus is reabsorbed in the proximal tubule via an active process, primarily conducted by sodium-glucose linked co-transporters (SGLTs) [10]. Two types of SGLTs, SGLT1 and SGLT2, are responsible for this process, the majority of which (80–90%), is managed by SGLT2s [11]. By inhibiting SGLT2, the plasma threshold for glucose excretion is lowered, which promotes Correspondence to: Neeta B. Amin, PharmD, CVMED Research Unit, Pfizer Worldwide Research and Development, 610 Main Street, Mail Stop 004-403, Cambridge, MA 02139, USA. E-mail: [email protected] ∗
During the time of study conduct
glucosuria, thereby reducing the level of hyperglycaemia [8]. Consequently, SGLT2 has become an important therapeutic target and several SGLT2-selective inhibitors are either approved or in clinical development for the management of blood glucose in patients with T2DM [12–17]. In clinical studies, SGLT2 inhibitors have been well tolerated, with the most common adverse events (AEs) being an increase in urinary tract infections (UTIs) and/or genital fungal infections (GFIs) [12–17]. The use of SGLT2 inhibitors also leads to modest reductions in blood pressure (BP) and body weight, which are favourable in this population [12–17]. Moreover, working via an insulin-independent mechanism distinct from metformin and other currently approved oral antidiabetic drugs (OADs) [8], SGLT2 inhibitors have the potential to be used concurrently with other treatment in patients who require more intensive regimens to lower blood glucose. Ertugliflozin (PF-04971729; Pfizer Inc., New York, NY, USA) is a highly selective inhibitor of SGLT2, with a 2000-fold in vitro selectivity for human SGLT2 over SGLT1 (half maximum inhibitory concentration: SGLT2, 0.877 nM vs SGLT1, 1960 nM) [18,19]. Ertugliflozin is rapidly absorbed after a single oral dose, with mean maximum plasma
ORIGINAL ARTICLE
Diabetes, Obesity and Metabolism 2015. © 2015 John Wiley & Sons Ltd
original article concentrations occurring after ∼1 h and is eliminated largely via glucuronidation [18,19]. Systemic exposure in humans is dose-proportional over the dose range 0.5–300 mg, with an elimination half-life of 11–17 h [19]. As ertugliflozin does not rely on exogenous or endogenous insulin to reduce blood glucose [9], it has the potential to provide improved long-term glycaemic control relative to other insulin-dependent OADs. The present phase II study sought to evaluate the dose–response of ertugliflozin (1–25 mg), administered once daily for 12 weeks, with regard to glycated haemoglobin (HbA1c) in patients with T2DM on stable doses of metformin.
Materials and Methods Study Design This 12-week, randomized, double-blind, placebo- and active-controlled, parallel group, double-dummy, dose-ranging study (NCT01059825) enrolled male and female patients with T2DM between 2 March 2010 and 20 January 2011, from 42 sites in five countries (Canada, 7 sites; India, 8 sites; Korea, 4 sites; Mexico, 5 sites; and USA, 18 sites). The study was conducted in compliance with the Declaration of Helsinki Good Clinical Practice guidelines. The relevant institutional review boards or independent ethics committees approved the protocol, and each participant provided written informed consent before enrolment. After screening, eligible patients entered a run-in period of at least 8 but no longer than 12 weeks, during which background glycaemic medications were stabilized to metformin (dose increments of 500 mg; maximum to not exceed 2500 mg/day, or 3000 mg/day where indicated in the country product label), other OADs were discontinued, and hypertension and/or dyslipidaemia treatments were stabilized. All treatments were stable by the time of randomization at visit 4 (Figure S1). Patients were randomized, using a computer-generated random permuted block method, to one of six blinded treatment regimens for the 12-week treatment period: once-daily ertugliflozin (1, 5, 10 or 25 mg); sitagliptin (100 mg; positive control) or placebo. Patients were instructed to take study medication at the same time each day with their morning meal. Patients returned for a follow-up visit at least 14 days following the final dose.
Patient Population Eligible patients were aged 18–70 years (or 21–70 years based on country-specific age of consent) with T2DM according to American Diabetes Association criteria [20] and body mass index 23–45 kg/m2 . For at least 6 weeks before screening, T2DM was managed on a stable dose of metformin, either alone or with an acceptable OAD as long as the latter was discontinued for at least 8 weeks before randomization and for the duration of study participation. At screening, eligible patients had HbA1c concentrations of 7.0–11.0% (if on metformin monotherapy) or 6.5–9.5% (if on metformin plus one OAD, excluding thiazolidinediones), and fasting plasma glucose (FPG)
Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin N. B. Amin1 , X. Wang1,∗ , S. M. Jain2 , D. S. Lee1 , G. Nucci1 & J. M. Rusnak1 1 Pfizer Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA 2 TOTALL Diabetes Hormone Institute, Indore, India
Aim: To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored. Results: Ertugliflozin (1–25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) −0.45% (1 mg) to −0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (−0.76%; p = 0.0001)], FPG (LSM −1.17 to −1.90 mmol/l; p < 0.0001) and body weight (−1.15 to −2.15%; p < 0.0001). The LSM SBP decreased by −3.4 to −4.0 mmHg from baseline with ertugliflozin 5–25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo. Conclusion: Ertugliflozin (1–25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated. Keywords: ertugliflozin, HbA1c, PF-04971729, sodium-glucose linked co-transporter (SGLT), type 2 diabetes mellitus (T2DM) Date submitted 12 December 2014; date of first decision 6 January 2015; date of final acceptance 3 March 2015
Introduction In 2013, an estimated 382 million people had diabetes [1] and the World Health Organization predicts that, by 2030, diabetes will be the seventh leading cause of death [2]. Metformin is a recommended first-line therapy for type 2 diabetes (T2DM) [3,4], but the progressive nature of diabetes frequently necessitates more intensive, or combination treatment regimens to reach and/or maintain glycaemic control [4] and to reduce the risk factors for cardiovascular complications [5–7]. In the maintenance of glucose homeostasis by the kidney [8,9], glucose filtered at the glomerulus is reabsorbed in the proximal tubule via an active process, primarily conducted by sodium-glucose linked co-transporters (SGLTs) [10]. Two types of SGLTs, SGLT1 and SGLT2, are responsible for this process, the majority of which (80–90%), is managed by SGLT2s [11]. By inhibiting SGLT2, the plasma threshold for glucose excretion is lowered, which promotes Correspondence to: Neeta B. Amin, PharmD, CVMED Research Unit, Pfizer Worldwide Research and Development, 610 Main Street, Mail Stop 004-403, Cambridge, MA 02139, USA. E-mail: [email protected] ∗
During the time of study conduct
glucosuria, thereby reducing the level of hyperglycaemia [8]. Consequently, SGLT2 has become an important therapeutic target and several SGLT2-selective inhibitors are either approved or in clinical development for the management of blood glucose in patients with T2DM [12–17]. In clinical studies, SGLT2 inhibitors have been well tolerated, with the most common adverse events (AEs) being an increase in urinary tract infections (UTIs) and/or genital fungal infections (GFIs) [12–17]. The use of SGLT2 inhibitors also leads to modest reductions in blood pressure (BP) and body weight, which are favourable in this population [12–17]. Moreover, working via an insulin-independent mechanism distinct from metformin and other currently approved oral antidiabetic drugs (OADs) [8], SGLT2 inhibitors have the potential to be used concurrently with other treatment in patients who require more intensive regimens to lower blood glucose. Ertugliflozin (PF-04971729; Pfizer Inc., New York, NY, USA) is a highly selective inhibitor of SGLT2, with a 2000-fold in vitro selectivity for human SGLT2 over SGLT1 (half maximum inhibitory concentration: SGLT2, 0.877 nM vs SGLT1, 1960 nM) [18,19]. Ertugliflozin is rapidly absorbed after a single oral dose, with mean maximum plasma
ORIGINAL ARTICLE
Diabetes, Obesity and Metabolism 2015. © 2015 John Wiley & Sons Ltd
original article concentrations occurring after ∼1 h and is eliminated largely via glucuronidation [18,19]. Systemic exposure in humans is dose-proportional over the dose range 0.5–300 mg, with an elimination half-life of 11–17 h [19]. As ertugliflozin does not rely on exogenous or endogenous insulin to reduce blood glucose [9], it has the potential to provide improved long-term glycaemic control relative to other insulin-dependent OADs. The present phase II study sought to evaluate the dose–response of ertugliflozin (1–25 mg), administered once daily for 12 weeks, with regard to glycated haemoglobin (HbA1c) in patients with T2DM on stable doses of metformin.
Materials and Methods Study Design This 12-week, randomized, double-blind, placebo- and active-controlled, parallel group, double-dummy, dose-ranging study (NCT01059825) enrolled male and female patients with T2DM between 2 March 2010 and 20 January 2011, from 42 sites in five countries (Canada, 7 sites; India, 8 sites; Korea, 4 sites; Mexico, 5 sites; and USA, 18 sites). The study was conducted in compliance with the Declaration of Helsinki Good Clinical Practice guidelines. The relevant institutional review boards or independent ethics committees approved the protocol, and each participant provided written informed consent before enrolment. After screening, eligible patients entered a run-in period of at least 8 but no longer than 12 weeks, during which background glycaemic medications were stabilized to metformin (dose increments of 500 mg; maximum to not exceed 2500 mg/day, or 3000 mg/day where indicated in the country product label), other OADs were discontinued, and hypertension and/or dyslipidaemia treatments were stabilized. All treatments were stable by the time of randomization at visit 4 (Figure S1). Patients were randomized, using a computer-generated random permuted block method, to one of six blinded treatment regimens for the 12-week treatment period: once-daily ertugliflozin (1, 5, 10 or 25 mg); sitagliptin (100 mg; positive control) or placebo. Patients were instructed to take study medication at the same time each day with their morning meal. Patients returned for a follow-up visit at least 14 days following the final dose.
Patient Population Eligible patients were aged 18–70 years (or 21–70 years based on country-specific age of consent) with T2DM according to American Diabetes Association criteria [20] and body mass index 23–45 kg/m2 . For at least 6 weeks before screening, T2DM was managed on a stable dose of metformin, either alone or with an acceptable OAD as long as the latter was discontinued for at least 8 weeks before randomization and for the duration of study participation. At screening, eligible patients had HbA1c concentrations of 7.0–11.0% (if on metformin monotherapy) or 6.5–9.5% (if on metformin plus one OAD, excluding thiazolidinediones), and fasting plasma glucose (FPG)
