Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in type 2 diabetes patients: 4-year data Stefano Del Prato1, Michael Nauck2, Santiago Durán-Garcia3, Laura Maffei4, Katja Rohwedder5, Anett Theuerkauf6, Shamik Parikh7 1
University of Pisa, Pisa, Italy
2
Diabetes Center, Bad Lauterberg, Germany
3
Hospital Universitario de Valme, Seville, Spain
4
CADE-ICA, Argentina
5
AstraZeneca, Wedel, Germany
6
Aptiv Solutions, Cologne, Germany
7
AstraZeneca, Gaithersburg, Maryland USA
Correspondence to: Stefano Del Prato, MD, PhD; Department of Clinical and Experimental Medicine, Section of Diabetes, Ospedale Cisanello, Via Paradisa, 2, 56124, Pisa, Italy E-mail: [email protected]
Short running title: Long-term efficacy of dapagliflozin versus sulphonylurea as add-on to metformin.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12459
This article is protected by copyright. All rights reserved
Abstract Aims: To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Study findings at 52 and 104 weeks (NCT00660907) showed that dapagliflozin had similar glycaemic efficacy to glipizide and was associated with weight loss and lower incidence of hypoglycaemia. The 4-year data are now reported. Methods: This was an extension of the earlier randomized, double-blind, phase 3 study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatmentgroup comparisons were calculated. Results: At 208 weeks, dapagliflozin produced sustained reductions in HbA1c (–0.30% [95% confidence interval (CI), –0.51 to –0.09]), total body weight (–4.38 kg [95% CI –5.31 to –3.46]) and systolic blood pressure (SBP; –3.67 mmHg [95% CI –5.92 to –1.41]), compared with glipizide. The HbA1c coefficient of failure was significantly lower for dapagliflozin than glipizide (0.19 [95% CI 0.12–0.25] vs. 0.61 [0.49–0.72], difference, –0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in glipizidetreated patients. Fewer patients reported hypoglycaemia with dapagliflozin compared with glipizide (5.4% vs. 51.5%). Genital and urinary tract infections were more common with dapagliflozin than glipizide, but incidence decreased with time and all events responded well to antimicrobial treatment. Conclusions: In patients completing 4 years of treatment, dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide. Keywords: dapagliflozin, efficacy, safety, SGLT2 inhibitor, type 2 diabetes, durability
This article is protected by copyright. All rights reserved
Introduction Durable glycaemic control is critical to morbidity and mortality risk reduction in the long-term management of patients with type 2 diabetes. Oral metformin is often used as first-line treatment [1] but loss of glucose-lowering efficacy over time is common [2], and stepwise therapy intensification with a sulphonylurea (SU) and/or insulin add-on therapy may be required to restore glycaemic control [3]. However, loss of SU glucose-lowering efficacy can occur after only 1 year [2]. In addition, SU and insulin therapies are frequently associated with weight gain and an increased incidence of hypoglycaemia [1]. Poor treatment tolerability may result in poor patient adherence to treatment and further deterioration of glycaemic control.[4,5] Dapagliflozin is a highly selective renal sodium-glucose co-transporter 2 (SGLT2) inhibitor [6] that lowers blood glucose in a dose-dependent, insulin-independent, manner [7]. SGLT2 inhibitors act by reducing renal glucose reabsorption from the proximal tubule, promoting excretion of excess glucose, net calorie loss, and improved glycaemic control [6,8,9]. Dapagliflozin was approved in the European Union in 2012 [10] and in the United States in 2014 [11]. To evaluate the long-term efficacy and tolerability of dapagliflozin, planned extensions to the original 52-week study included evaluations to 104 weeks (2 years) and now to 208 weeks (4 years). At 2 years, dapagliflozin demonstrated sustained glycaemic efficacy and mean body weight reduction, and 10-fold fewer hypoglycaemic events, compared with glipizide [12]. Dapagliflozin may therefore be a valuable alternative to existing add-on therapies – by improving glycaemic control with few adverse effects. The 4-year efficacy and tolerability findings of this study are now described. This is the longest clinical study of an SGLT2 inhibitor compared with a commonly prescribed sulphonylurea as add-on to metformin for the treatment of type 2 diabetes to date.
Methods Study Design This was an international, randomized, double-blind, multicentre, phase 3 study lasting 208 weeks (4 years). The initial 52-week study was conducted at 95 sites in 10 countries and was followed by two extension periods, the first lasting 52 weeks, and the second lasting 104 weeks (Figure S1). Core methods, randomization, and
This article is protected by copyright. All rights reserved
blinding procedures, as well as inclusion and exclusion criteria, have previously been described [13]. Study sites and participants remained blinded to study medication throughout the entire 208-week study. Patients who completed the first 104-week period, and had given documented informed consent, were eligible to continue into the second 104-week, double-blind extension period. The study complied with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines. It was approved by institutional review boards and independent ethics committees for the participating centres, and it is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent before entering the study. Treatments and Interventions Patients continued to receive their randomly assigned medication, either dapagliflozin (2.5, 5 or 10 mg) or glipizide (5, 10 or 20 mg), combined with open-label metformin (1500–2500 mg/day), as well as lifestyle advice. If HbA1c was ≥7.0%, a single up-titration of study medication was permitted. Study medication could be down-titrated to mitigate recurrent hypoglycaemia at any time during both study extensions to 208 weeks. Rescue medication was mandatory if HbA1c between 104 and 208 weeks was ≥8.0%, and was at the investigator’s discretion if HbA1c was between 7.0% and 8.0%. Patients continued in the study following glycaemic rescue but further up-titration of study medication was prohibited. Study medication was stopped at 208 weeks, and patients were treated according to clinical judgment thereafter. Endpoints and Safety Assessments All variables analysed for the 52-week period were re-examined during the study extensions. All analyses during the extension periods were considered exploratory. All endpoints were reported as changes from a specific time-point to weeks 52, 104 and 208. Glycaemic response was analysed in all patients based on baseline HbA1c: >6.5%, ≥7.0%,
University of Pisa, Pisa, Italy
2
Diabetes Center, Bad Lauterberg, Germany
3
Hospital Universitario de Valme, Seville, Spain
4
CADE-ICA, Argentina
5
AstraZeneca, Wedel, Germany
6
Aptiv Solutions, Cologne, Germany
7
AstraZeneca, Gaithersburg, Maryland USA
Correspondence to: Stefano Del Prato, MD, PhD; Department of Clinical and Experimental Medicine, Section of Diabetes, Ospedale Cisanello, Via Paradisa, 2, 56124, Pisa, Italy E-mail: [email protected]
Short running title: Long-term efficacy of dapagliflozin versus sulphonylurea as add-on to metformin.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12459
This article is protected by copyright. All rights reserved
Abstract Aims: To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Study findings at 52 and 104 weeks (NCT00660907) showed that dapagliflozin had similar glycaemic efficacy to glipizide and was associated with weight loss and lower incidence of hypoglycaemia. The 4-year data are now reported. Methods: This was an extension of the earlier randomized, double-blind, phase 3 study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatmentgroup comparisons were calculated. Results: At 208 weeks, dapagliflozin produced sustained reductions in HbA1c (–0.30% [95% confidence interval (CI), –0.51 to –0.09]), total body weight (–4.38 kg [95% CI –5.31 to –3.46]) and systolic blood pressure (SBP; –3.67 mmHg [95% CI –5.92 to –1.41]), compared with glipizide. The HbA1c coefficient of failure was significantly lower for dapagliflozin than glipizide (0.19 [95% CI 0.12–0.25] vs. 0.61 [0.49–0.72], difference, –0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in glipizidetreated patients. Fewer patients reported hypoglycaemia with dapagliflozin compared with glipizide (5.4% vs. 51.5%). Genital and urinary tract infections were more common with dapagliflozin than glipizide, but incidence decreased with time and all events responded well to antimicrobial treatment. Conclusions: In patients completing 4 years of treatment, dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide. Keywords: dapagliflozin, efficacy, safety, SGLT2 inhibitor, type 2 diabetes, durability
This article is protected by copyright. All rights reserved
Introduction Durable glycaemic control is critical to morbidity and mortality risk reduction in the long-term management of patients with type 2 diabetes. Oral metformin is often used as first-line treatment [1] but loss of glucose-lowering efficacy over time is common [2], and stepwise therapy intensification with a sulphonylurea (SU) and/or insulin add-on therapy may be required to restore glycaemic control [3]. However, loss of SU glucose-lowering efficacy can occur after only 1 year [2]. In addition, SU and insulin therapies are frequently associated with weight gain and an increased incidence of hypoglycaemia [1]. Poor treatment tolerability may result in poor patient adherence to treatment and further deterioration of glycaemic control.[4,5] Dapagliflozin is a highly selective renal sodium-glucose co-transporter 2 (SGLT2) inhibitor [6] that lowers blood glucose in a dose-dependent, insulin-independent, manner [7]. SGLT2 inhibitors act by reducing renal glucose reabsorption from the proximal tubule, promoting excretion of excess glucose, net calorie loss, and improved glycaemic control [6,8,9]. Dapagliflozin was approved in the European Union in 2012 [10] and in the United States in 2014 [11]. To evaluate the long-term efficacy and tolerability of dapagliflozin, planned extensions to the original 52-week study included evaluations to 104 weeks (2 years) and now to 208 weeks (4 years). At 2 years, dapagliflozin demonstrated sustained glycaemic efficacy and mean body weight reduction, and 10-fold fewer hypoglycaemic events, compared with glipizide [12]. Dapagliflozin may therefore be a valuable alternative to existing add-on therapies – by improving glycaemic control with few adverse effects. The 4-year efficacy and tolerability findings of this study are now described. This is the longest clinical study of an SGLT2 inhibitor compared with a commonly prescribed sulphonylurea as add-on to metformin for the treatment of type 2 diabetes to date.
Methods Study Design This was an international, randomized, double-blind, multicentre, phase 3 study lasting 208 weeks (4 years). The initial 52-week study was conducted at 95 sites in 10 countries and was followed by two extension periods, the first lasting 52 weeks, and the second lasting 104 weeks (Figure S1). Core methods, randomization, and
This article is protected by copyright. All rights reserved
blinding procedures, as well as inclusion and exclusion criteria, have previously been described [13]. Study sites and participants remained blinded to study medication throughout the entire 208-week study. Patients who completed the first 104-week period, and had given documented informed consent, were eligible to continue into the second 104-week, double-blind extension period. The study complied with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines. It was approved by institutional review boards and independent ethics committees for the participating centres, and it is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent before entering the study. Treatments and Interventions Patients continued to receive their randomly assigned medication, either dapagliflozin (2.5, 5 or 10 mg) or glipizide (5, 10 or 20 mg), combined with open-label metformin (1500–2500 mg/day), as well as lifestyle advice. If HbA1c was ≥7.0%, a single up-titration of study medication was permitted. Study medication could be down-titrated to mitigate recurrent hypoglycaemia at any time during both study extensions to 208 weeks. Rescue medication was mandatory if HbA1c between 104 and 208 weeks was ≥8.0%, and was at the investigator’s discretion if HbA1c was between 7.0% and 8.0%. Patients continued in the study following glycaemic rescue but further up-titration of study medication was prohibited. Study medication was stopped at 208 weeks, and patients were treated according to clinical judgment thereafter. Endpoints and Safety Assessments All variables analysed for the 52-week period were re-examined during the study extensions. All analyses during the extension periods were considered exploratory. All endpoints were reported as changes from a specific time-point to weeks 52, 104 and 208. Glycaemic response was analysed in all patients based on baseline HbA1c: >6.5%, ≥7.0%,
