Durability of glycaemic efficacy over 2 years with dapagliflozin versus
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glipizide as add-on therapies in patients whose type 2 diabetes mellitus was inadequately controlled with metformin Michael A. Nauck, MD1, Stefano Del Prato, MD2, Santiago Durán-García, MD, PhD3, Katja Rohwedder, MD4, Anna Maria Langkilde, MD5, Jennifer Sugg, MS6, Shamik J. Parikh, MD6 1
Diabetes Centre, Bad Lauterberg, Germany; 2Department of Endocrinology and Metabolism,
Section of Diabetes and Metabolic Diseases, University of Pisa, Pisa, Italy; 3Hospital Universitario de Valme, Seville, Spain; 4AstraZeneca, Wedel, Germany; 5AstraZeneca, M lndal, Sweden; 6
AstraZeneca, Wilmington, Delaware, United States
Corresponding author: Prof. Dr. med. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany. Tel: +49-5524-81218; Fax: +49-5524-81398; Email: [email protected]
NCT00660907, ClinicalTrials.gov
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.12327
This article is protected by copyright. All rights reserved.
ABSTRACT AIMS: To assess long-term glycaemic durability, safety and tolerability of dapagliflozin versus
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glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS: This was a 52-week, randomized, double-blind study of dapagliflozin (n=406) versus glipizide (n=408), up-titrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 mg/day and 20 mg/day, respectively, as add-on therapies to metformin (≥1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. RESULTS: In total, 53.1% of patients completed 104 weeks. Following the greater initial (0-18week) HbA1c drop with glipizide, the 18-104-week HbA1c Coefficient of Failure (CoF) was lower with dapagliflozin (0.13%/year) compared with glipizide (0.59%/year), resulting in significant dapagliflozin vs glipizide differences of −0.46%/year (95%CI: −0.60,−0.33; p=0.0001) for CoF and −0.18%[−2.0mmol/mol] (95%CI: −0.33[−3.6],−0.03[−0.3]; p=0.021) for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure (SBP), whereas glipizide increased weight and SBP, giving 104-week dapagliflozin vs glipizide differences of −5.1kg (95%CI: −5.7,−4.4) and −3.9mmHg (95%CI: −6.1,−1.7), respectively. Over 104 weeks, the hypoglycaemia rate was tenfold less with dapagliflozin compared with glipizide (4.2 vs 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection (UTI) were greater with dapagliflozin (14.8 and 13.5%, respectively) compared with glipizide (2.9 and 9.1%, respectively). CONCLUSIONS: Over 2 years, compared with glipizide, dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and SBP, and a low hypoglycaemia rate; however, genital infection and UTI rates occurred more frequently. NCT00660907, ClinicalTrials.gov
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INTRODUCTION The goal of durable glycaemic control in order to reduce the long-term risk of diabetes-related
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morbidity and mortality remains a central therapeutic challenge for the management of patients with type 2 diabetes. Drug therapy may fail, either initially or over time [1], requiring treatment intensification [2]. Despite this, many patients fail to achieve and/or maintain glycaemic targets [3-6] for a variety of reasons that may include disease progression and therapy-, patient-, or physicianrelated factors. Of particular importance is poor patient adherence secondary to actual and/or feared side effects of therapy, especially those of hypoglycaemia and weight gain, which are commonly associated with sulfonylurea or insulin therapy [7-9]. Dapagliflozin, a highly selective inhibitor of renal sodium-glucose cotransporter 2 (SGLT2) [10,11], lowers blood glucose in patients with type 2 diabetes [12] by reducing renal glucose reabsorption and increasing urinary glucose excretion in a manner dependent upon blood glucose level and glomerular filtration rate [13]. Consequent to its insulin-independent mechanism of action, the risk of hypoglycaemia with dapagliflozin is low [14] and it potentially provides consistent and durable efficacy at any stage of beta-cell failure. In addition, glucosuria-related caloric loss and osmotic diuresis are associated with weight loss [15] and reduced blood pressure [16]. A previous report of the current study, directly comparing dapagliflozin with glipizide as add-on therapies to metformin in patients whose type 2 diabetes was inadequately controlled on metformin, established non-inferiority for HbA1c reduction at 1 year but divergent effects on hypoglycaemia and weight [17]. Here, the long-term durability of glycaemic efficacy, rates of hypoglycaemia, changes in weight, blood pressure and other clinically relevant efficacy and safety parameters are compared between the two active treatments in an extension of this study after a total of two years of therapy.
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RESEARCH DESIGN AND METHODS A detailed description of study methods has been previously published [17]; a brief overview is
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provided here.
Study design This was a 52-week randomized, double-blind, parallel-group, active-controlled, non-inferiority trial with a 156-week extension period that evaluated dapagliflozin versus glipizide as add-on therapies to metformin in adult patients whose Type 2 diabetes was inadequately controlled on metformin alone. The study complied with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines, was approved by institutional review boards and independent ethics committees for the participating centres, and is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent. Results from the 52-week short-term double-blind treatment period have been previously reported [17]. Here, data including the 52-week double-blind extension period after a total of 2 years of treatment are reported.
Inclusion criteria The principal inclusion criteria were: men and women aged ≥18 years with an HbA1c >6.5 and ≤10%; fasting plasma glucose (FPG) ≤15 mmol/L; C-peptide concentration of ≥0.33 nmol/L; and metformin, or metformin plus one other oral antidiabetic drug (OAD), administered up to half-maximal dose for at least 8 weeks before enrolment. Full details on inclusion and exclusion criteria have been previously reported [17].
Treatments and interventions Eligible patients discontinued other OADs and were stabilized on ≥1500 mg of open-label metformin daily, after which no further changes in metformin dose were allowed. After a 2-week single-blind lead-in period, patients were randomized 1:1 to receive double-blind dapagliflozin or glipizide
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treatment. Details of procedures for randomization, allocation concealment and blinding have been previously published [17]. Patients commenced at dapagliflozin 2.5 mg or glipizide at 5 mg and could be up-titrated over the initial 18 weeks if FPG was ≥6.1 mmol/L to a maximum tolerated dose of 10
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mg and 20 mg, respectively. Treatment was then maintained without further up-titration until the primary analysis point at 52 weeks. Patients then entered the long-term double-blind extension period for a further 52 weeks of doubleblind treatment. During this period one single attempt at up-titration was allowed if HbA1c was >7%, but only if the patient had not already reached the maximum dose. During all study periods, downtitration was allowed in the event of recurrent hypoglycaemia. Patients with inadequate glycaemic control at maximum dose were discontinued from the study based upon time-dependent criteria; those during the 52-week double-blind treatment period were based upon FPG levels and have been previously reported [17]; those during the subsequent 52-week extension period were FPG >11.1 mmol/L and HbA1c ≥8%. As metformin therapy is contraindicated with renal impairment, patients were discontinued if calculated creatinine clearance using the Cockcroft-Gault equation [18] was 10 years, mean HbA1c was 7.72% [61 mmol/mol] with 10.7% of patients having a baseline HbA1c ≥9.0% [75 mmol/mol], mean FPG was 9.05 mmol/L, mean weight and body mass index (BMI) were 88.0 kg and 31.5 kg/m2, respectively, with 56.2% of patients presenting with a BMI ≥30 kg/m2.
Efficacy Durability of glycaemic control As previously reported, the HbA1c adjusted mean change from baseline with dapagliflozin was statistically non-inferior to glipizide at 52 weeks, with both treatments reducing HbA1c by −0.52% [−5.7 mmol/mol] [17]. The initial mean HbA1c reduction from baseline at 52 weeks was mostly sustained with dapagliflozin at 104 weeks (−0.32% [3.5 mmol/mol]; 95% CI: −0.42 [−4.6], −0.21 [−2.3]), but had attenuated with glipizide (−0.14% [1.5 mmol/mol]; 95% CI: −0.25 [−2.7], −0.03 [−0.3]) (Fig. 1A), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −0.18% [2.0 mmol/mol] (95% CI: −0.33 [−3.6], −0.03 [−0.3]; p=0.0211).
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The initial mean FPG reduction from baseline at the end of the titration period at 18 weeks (−1.12 mmol/L with dapagliflozin and −1.59 mmol/L with glipizide) was sustained with dapagliflozin at 104 (−1.12 mmol/L; 95% CI:−1.32, −0.92), but had attenuated with glipizide (−0.68 mmol/L; 95%
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CI:−0.89, −0.47) (Fig. 1B), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −0.44 mmol/L (95% CI: −0.73, −0.15; p=0.0030). Fewer patients were down-titrated or were discontinued due to inadequate glycaemic control with dapagliflozin compared with glipizide treatment (Table 1). Mean dose levels at the end of the 18week titration period for dapagliflozin and glipizide were 9.2 mg and 16.4 mg, respectively. Corresponding values at 104 weeks were 9.2 mg and 15.9 mg, respectively. The CoF slopes for dapagliflozin were significantly lower compared with glipizide, irrespective of which glycaemic variable (HbA1c or FPG) or analysis set was employed (Figs. 1C and 1D, Supplementary Table A1). Using the full analysis set, CoF for HbA1c from 18-104 weeks showed a rise of 0.13%/year [1.4 mmol/mol/year] (95% CI: 0.06 [0.7], 0.20 [2.2]) with dapagliflozin and a rise of 0.59%/year [6.4 mmol/mol/year] (95% CI: 0.48 [ 5.2], 0.71 [7.8]) with glipizide, resulting in a dapagliflozin vs glipizide difference of −0.46%/year [−5.0 mmol/mol/year] (95%CI: −0.60 [−6.6], −0.33 [−3.6]; p=0.0001). Corresponding values for FPG were 0.28 mmol/L/year (95% CI: 0.10, 0.46), 0.77 mmol/L/year (95% CI: 0.50, 1.04), and −0.48 mmol/L/year (95% CI: −0.81, −0.16; p=0.0033), respectively. Using the completers analysis set, CoF slopes for HbA1c and FPG were smaller in magnitude for both treatments, giving dapagliflozin CoF 18-52 week slopes that were not significantly different from zero (Figs. 1C and 1D). Comparisons of CoF slopes for HbA1c between 18-52 and 52-104 weeks, showed significant dapagliflozin versus glipizide differences for both time periods, irrespective of which analysis set was employed (Supplementary Table A1). The post hoc CoF sensitivity analysis of completers who were also not down-titrated produced very similar results to the CoF analysis of completers, irrespective of down-titration (Supplementary Table A1, and Supplementary Fig. A2).
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Maintenance of changes in weight The initial mean weight reduction from baseline at 52 weeks with dapagliflozin (−3.4 kg) and weight
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gain with glipizide (1.6 kg) remained relatively stable at 104 weeks with dapagliflozin (−3.7 kg; 95% CI: −4.2, −3.2) and glipizide (1.4 kg; 95% CI: 0.9, 1.8) (Fig. 1E), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −5.1 kg (95% CI: −5.7, −4.4). The proportion of patients achieving weight reduction ≥5% with dapagliflozin at 104 weeks was 23.8% (95% CI: 19.6, 27.9) and with glipizide was 2.8% (95% CI: 1.2, 4.4), resulting in a dapagliflozin versus glipizide difference at 104 weeks of 21.0 percentage points (95% CI: 16.5, 25.5).
Changes in blood pressure The initial mean seated systolic blood pressure reduction from baseline at 52 weeks with dapagliflozin (−3.8 mmHg) and increase in blood pressure with glipizide (0.9 mmHg) remained mostly stable at 104 weeks with dapagliflozin (−2.7 mmHg; 95% CI: −4.2, −1.2) and glipizide (1.2 mmHg; 95% CI: −0.4, 2.8) (Fig. 1F), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −3.9 mmHg (95% CI: −6.1, −1.7).
Changes in urinary glucose excretion Dapagliflozin produced sustained increases in urinary glucose excretion over 104 weeks, as expected from its mechanism of action (Supplementary Fig. A3).
Safety and tolerability Hypoglycaemia The proportion of patients experiencing at least one hypoglycemic episode over 104 weeks was tenfold less with dapagliflozin, 17/406 (4.2%), than with glipizide, 187/408 (45.8%), with the majority of first episodes occurring during the first 18 weeks of treatment (Figure 2A).
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When analysed by total number of hypoglycemic events, 26 events were observed with dapagliflozin versus 843 events with glipizide over 104 weeks, with the majority of these events occurring during
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the first 18 weeks of treatment (Figure 2B). Among patients who experienced hypoglycaemia, the mean number and inter-individual variability of these events over 104 weeks was lower with dapagliflozin (mean, 1.5; standard deviation, 1.2; minimum, 1; maximum, 5) compared with glipizide (mean, 4.5; standard deviation, 5.7; minimum, 1; maximum, 38). No dapagliflozin-treated patients discontinued the study due to hypoglycaemia, whereas 7 glipizidetreated patients were discontinued for this reason (Tables 1 and 2).
Events suggestive of genital infection The proportion of patients experiencing events suggestive of genital infection over 104 weeks was 60/408 (14.8%) with dapagliflozin versus 12/408 (2.9%) with glipizide, with the majority of first episodes occurring during the first 52 weeks of treatment (Figure 2C). Genital infections were more common in women (Table 2). When analysed by total number of events suggestive of genital infection, 133 events were observed with dapagliflozin versus 14 events with glipizide over 104 weeks, with the majority of these events occurring during the first 52 weeks of treatment (Figure 2D). Of these events, 84.2% and 71.4% responded to initial standard treatment in the dapagliflozin and glipizide groups, respectively. Among patients who experienced events suggestive of genital infection over 104 weeks, the proportion of patients experiencing a single episode was 36/60 (60.0%) with dapagliflozin versus 10/12 (83.3%) with glipizide. The proportion of patients experiencing 2-3 events was 18/60 (30.0%) with dapagliflozin versus 2/12 (16.7%) with glipizide, and experiencing 4 or more events was 6/60 (10%) with dapagliflozin versus none with glipizide.
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Events suggestive of urinary tract infection The proportion of patients experiencing events suggestive of UTI over 104 weeks was 55/408 (13.5%)
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with dapagliflozin versus 37/408 (9.1%) with glipizide, with the majority of first episodes occurring during the first 52 weeks of treatment (Figure 2E). UTIs were more common in women (Table 2). When analysed by total number of events suggestive of UTI, 79 events were observed with dapagliflozin versus 50 events with glipizide over 104 weeks, with the majority of these events occurring during the first 52 weeks of treatment (Figure 2F). The rate of UTI from 52-104 weeks was comparable between the dapagliflozin (7.11/100 patient years; 95% CI: 4.28, 11.10) and glipizide (7.16/100 patient years; 95% CI: 4.24, 11.32) groups. Of these events, 89.7% and 84.2% responded to initial standard treatment, and 39.2% and 28.0% had a positive urine culture, in the dapagliflozin and glipizide groups, respectively. Among patients who experienced events suggestive of UTI over 104 weeks, the proportion of patients experiencing a single episode was 40/55 (72.7%) with dapagliflozin versus 27/37 (73.0%) with glipizide. The proportion of patients experiencing 2-3 events was 13/55 (23.6%) with dapagliflozin versus 10/27 (27.0%) with glipizide and experiencing 4-5 events was 2/55 (3.6%) with dapagliflozin versus none with glipizide. Kidney infections occurred in 3 patients treated with glipizide (2 pyelonephritis, 1 pyelocystitis/pyelonephritis) and in none treated with dapagliflozin.
General adverse event summary AEs and serious AEs (SAEs) were balanced across treatment groups (Table 1). SAEs considered related to study treatments were reported in 8 patients in the dapagliflozin group (complex ventricular arrhythmia, myocardial ischemia, decreased calculated creatinine clearance, epigastric pain, prostate cancer, pancreatic carcinoma, pulmonary embolism, and worsening of coronary artery disease) and in 7 patients in the glipizide group (3 SAEs of hypoglycaemia and one each of pyelonephritis, coronary artery occlusion, aortic aneurysm, bladder calculus).
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No deaths were reported in patients receiving dapagliflozin. Four deaths were reported in the group receiving glipizide due to mesenteric infarction, sudden death at home without autopsy, acute
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myocardial infarction, and road traffic accident. A total of 7 (3 prostate, 1 breast, 1 gastric and 2 pancreatic) and 3 (1 prostate, 1 skin, 1 lung) malignancies occurred during the 104 week study period in the dapagliflozin and glipizide groups, respectively (Table 2 and Supplementary Table A2).
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DISCUSSION Glycaemic durability over a 2-year period was significantly better with dapagliflozin compared with
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glipizide as demonstrated by Coefficient of Failure (CoF) slopes indicating a lower rate of HbA1c rise with dapagliflozin therapy. However, differential rates of discontinuation due to lack of glycaemic control or of down-titration or discontinuation due to hypoglycaemia, which were all higher in the glipizide arm, could partially explain the observed differences in CoF between the dapagliflozin and glipizide when estimated using the full analysis set only. Against this possibility, HbA1c in patients who completed the study and who were not down-titrated also showed an upward drift in HbA1c after the end of the titration period with glipizide, whereas HbA1c remained stable with dapagliflozin (Supplementary Fig. A2). Moreover, CoF with dapagliflozin using this latter analysis showed no significant rise in HbA1c over 2 years, whereas the rise in HbA1c remained significant with glipizide (Supplementary Table A1). In addition, up-titration during the long-term double-blind extension period, which occurred rarely but nevertheless more frequently with glipizide (Table 1), would have been expected to have produced CoF values more favourable to glipizide treatment, which was not the case. Taken together, these findings would suggest that, although the initial HbA1c drop was less with dapagliflozin compared with glipizide, long-term durability was greater with dapagliflozin treatment. Dapagliflozin demonstrated a low propensity to cause hypoglycaemia; the proportion of patients with episodes was 10-fold less with dapagliflozin compared with glipizide. For both treatments, hypoglycaemia was less frequent during the second year compared with the first year. However, this finding may have been influenced by rising HbA1c in the second year and/or poor patient recollection secondary to the increased time interval between study visits during the second year. It is noteworthy that among dapagliflozin-treated patients who had hypoglycemic episodes, the variability was low (a maximum of 5 episodes in any one patient), whereas among the higher number of glipizide-treated patients who had hypoglycemic episodes, variability was high (a maximum of 38 episodes in any one patient). This high number of episodes in a proportion of glipizide-treated patients was disturbing, as is reflected by the finding that 7 patients discontinued glipizide due to hypoglycaemia whereas none discontinued for this reason with dapagliflozin treatment (Table 2).
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The long-term glycaemic durability of dapagliflozin therapy (Fig. 1A-1D) and low rate of hypoglycaemia are likely to result from sustained urinary glucose excretion (Supplementary Fig. A3), which is neither influenced by changes in beta-cell secretory activity nor by changes in insulin
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sensitivity over time, whereas the lack of durability with glipizide is likely to have resulted from its dependence upon beta-cell function. In addition, persistent weight loss (Fig. 1E) and systolic blood pressure reduction (Fig. 1F) are likely to result from the urinary caloric loss and diuresis induced by dapagliflozin, respectively. These latter effects could indicate that dapagliflozin may potentially exert a beneficial effect on cardiovascular risk, as suggested by a meta-analysis of 14 dapagliflozin clinical trials of up to 2 years duration in which the hazard ratio for a composite endpoint of cardiovascular death, myocardial infarction, stroke or hospitalization for unstable angina was 0.82 (95% CI: 0.58, 1.15) [21]. However, full evaluation of the potential cardiovascular benefit/safety of dapagliflozin must await the outcome of the recently initiated DECLARE outcomes trial. Current treatment guidelines recommend the addition of a sulfonylurea, a thiazolidinedione, a dipeptidyl-peptidase IV (DPP-4) inhibitor, a glucagon-like peptide 1 (GLP-1) agonist, or insulin (in no particular preferential order) when metformin monotherapy fails [2]. Data directly comparing measures of glycaemic durability between sulfonylurea therapy and other oral glucose-lowering agents has demonstrated lower rates of HbA1c rise with pioglitazone [22], acarbose [22], and the DPP-4 inhibitors, saxagliptin [23], sitagliptin [24] and vildagliptin [25]. In the current report, glycaemic durability with dapagliflozin assessed over 2 years (CoF: HbA1c increase of 0.05%/year, completers analysis set) was significantly better than with glipizide (CoF: HbA1c increase of 0.28%/year, completers analysis set) and compares favourably with equivalent published data on per-protocol CoF slopes for saxagliptin showing an HbA1c increase of 0.05%/year [23] and for sitagliptin of 0.16%/year [24] assessed over 1 and 2-year periods, respectively. In addition, the dapagliflozin CoF HbA1c increase of 0.13%/year (full analysis set) compares favourably with recently published data on canagliflozin of a CoF HBA1c increase of 0.16%/year (modified intention-to-treat) over 2 years [26].The hypoglycaemia rate with dapagliflozin (4.2%) was comparable with published data on DPP-4 inhibitors (2.3-5%) [23-25], and much lower than with
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sulfonylureas (18.2-36.3%; 45.8%) [23,24,25;this report]. Weight loss with dapagliflozin was greater (3.7 kg) than in published data on DPP-4 inhibitors (0.3-1.6 kg) [23-25], whereas sulfonylureas produced weight gain (0.7-1.2 kg; 1.4 kg) [23,24,25;this report]. These data suggest that dapagliflozin
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can be considered a valuable alternative to sulfonylureas as an add-on therapy when metformin monotherapy fails to maintain glycaemic control. The lack of durable glycaemic efficacy, weight gain and hypoglycemic risk associated with sulfonylurea therapy, may explain why sulfonylureas are being used less today than in previous decades [27]. However, their low generic cost, together with trial data attesting some long-term benefits [28,29], contributes to their ongoing use despite increasing emphasis on the adverse event profile of sulfonylureas noted in guidelines [2,30]. As has been noted with the SGLT2-inhibitor class [15,17,31-38], events suggestive of genital infections and of UTIs, which included non-specific symptoms as well as clinically diagnosed infections, were more frequent with dapagliflozin compared with glipizide and were more commonly reported in women. Most of these infections were single episodes, most responded to routine management, and rarely led to study discontinuation. The rate of reported infection was lower in the second year of treatment, suggesting that adaptation to dapagliflozin exposure could occur, although poor patient recollection secondary to the increased time interval between study visits during the second year might explain this finding. Given that discontinuations due to infections were rare, the removal of patients at high risk of infection is an unlikely explanation for the reduced rate of infection in the second year. During the dapagliflozin clinical trial program, the overall proportion of patients with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.47%) and placebo/comparator (1.35%). Regarding differing tumours, the relative risk associated with dapagliflozin versus placebo/comparator was >1 for some tumours (bladder, prostate, breast) and
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glipizide as add-on therapies in patients whose type 2 diabetes mellitus was inadequately controlled with metformin Michael A. Nauck, MD1, Stefano Del Prato, MD2, Santiago Durán-García, MD, PhD3, Katja Rohwedder, MD4, Anna Maria Langkilde, MD5, Jennifer Sugg, MS6, Shamik J. Parikh, MD6 1
Diabetes Centre, Bad Lauterberg, Germany; 2Department of Endocrinology and Metabolism,
Section of Diabetes and Metabolic Diseases, University of Pisa, Pisa, Italy; 3Hospital Universitario de Valme, Seville, Spain; 4AstraZeneca, Wedel, Germany; 5AstraZeneca, M lndal, Sweden; 6
AstraZeneca, Wilmington, Delaware, United States
Corresponding author: Prof. Dr. med. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany. Tel: +49-5524-81218; Fax: +49-5524-81398; Email: [email protected]
NCT00660907, ClinicalTrials.gov
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.12327
This article is protected by copyright. All rights reserved.
ABSTRACT AIMS: To assess long-term glycaemic durability, safety and tolerability of dapagliflozin versus
Accepted Article
glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS: This was a 52-week, randomized, double-blind study of dapagliflozin (n=406) versus glipizide (n=408), up-titrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 mg/day and 20 mg/day, respectively, as add-on therapies to metformin (≥1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. RESULTS: In total, 53.1% of patients completed 104 weeks. Following the greater initial (0-18week) HbA1c drop with glipizide, the 18-104-week HbA1c Coefficient of Failure (CoF) was lower with dapagliflozin (0.13%/year) compared with glipizide (0.59%/year), resulting in significant dapagliflozin vs glipizide differences of −0.46%/year (95%CI: −0.60,−0.33; p=0.0001) for CoF and −0.18%[−2.0mmol/mol] (95%CI: −0.33[−3.6],−0.03[−0.3]; p=0.021) for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure (SBP), whereas glipizide increased weight and SBP, giving 104-week dapagliflozin vs glipizide differences of −5.1kg (95%CI: −5.7,−4.4) and −3.9mmHg (95%CI: −6.1,−1.7), respectively. Over 104 weeks, the hypoglycaemia rate was tenfold less with dapagliflozin compared with glipizide (4.2 vs 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection (UTI) were greater with dapagliflozin (14.8 and 13.5%, respectively) compared with glipizide (2.9 and 9.1%, respectively). CONCLUSIONS: Over 2 years, compared with glipizide, dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and SBP, and a low hypoglycaemia rate; however, genital infection and UTI rates occurred more frequently. NCT00660907, ClinicalTrials.gov
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INTRODUCTION The goal of durable glycaemic control in order to reduce the long-term risk of diabetes-related
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morbidity and mortality remains a central therapeutic challenge for the management of patients with type 2 diabetes. Drug therapy may fail, either initially or over time [1], requiring treatment intensification [2]. Despite this, many patients fail to achieve and/or maintain glycaemic targets [3-6] for a variety of reasons that may include disease progression and therapy-, patient-, or physicianrelated factors. Of particular importance is poor patient adherence secondary to actual and/or feared side effects of therapy, especially those of hypoglycaemia and weight gain, which are commonly associated with sulfonylurea or insulin therapy [7-9]. Dapagliflozin, a highly selective inhibitor of renal sodium-glucose cotransporter 2 (SGLT2) [10,11], lowers blood glucose in patients with type 2 diabetes [12] by reducing renal glucose reabsorption and increasing urinary glucose excretion in a manner dependent upon blood glucose level and glomerular filtration rate [13]. Consequent to its insulin-independent mechanism of action, the risk of hypoglycaemia with dapagliflozin is low [14] and it potentially provides consistent and durable efficacy at any stage of beta-cell failure. In addition, glucosuria-related caloric loss and osmotic diuresis are associated with weight loss [15] and reduced blood pressure [16]. A previous report of the current study, directly comparing dapagliflozin with glipizide as add-on therapies to metformin in patients whose type 2 diabetes was inadequately controlled on metformin, established non-inferiority for HbA1c reduction at 1 year but divergent effects on hypoglycaemia and weight [17]. Here, the long-term durability of glycaemic efficacy, rates of hypoglycaemia, changes in weight, blood pressure and other clinically relevant efficacy and safety parameters are compared between the two active treatments in an extension of this study after a total of two years of therapy.
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RESEARCH DESIGN AND METHODS A detailed description of study methods has been previously published [17]; a brief overview is
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provided here.
Study design This was a 52-week randomized, double-blind, parallel-group, active-controlled, non-inferiority trial with a 156-week extension period that evaluated dapagliflozin versus glipizide as add-on therapies to metformin in adult patients whose Type 2 diabetes was inadequately controlled on metformin alone. The study complied with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines, was approved by institutional review boards and independent ethics committees for the participating centres, and is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent. Results from the 52-week short-term double-blind treatment period have been previously reported [17]. Here, data including the 52-week double-blind extension period after a total of 2 years of treatment are reported.
Inclusion criteria The principal inclusion criteria were: men and women aged ≥18 years with an HbA1c >6.5 and ≤10%; fasting plasma glucose (FPG) ≤15 mmol/L; C-peptide concentration of ≥0.33 nmol/L; and metformin, or metformin plus one other oral antidiabetic drug (OAD), administered up to half-maximal dose for at least 8 weeks before enrolment. Full details on inclusion and exclusion criteria have been previously reported [17].
Treatments and interventions Eligible patients discontinued other OADs and were stabilized on ≥1500 mg of open-label metformin daily, after which no further changes in metformin dose were allowed. After a 2-week single-blind lead-in period, patients were randomized 1:1 to receive double-blind dapagliflozin or glipizide
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treatment. Details of procedures for randomization, allocation concealment and blinding have been previously published [17]. Patients commenced at dapagliflozin 2.5 mg or glipizide at 5 mg and could be up-titrated over the initial 18 weeks if FPG was ≥6.1 mmol/L to a maximum tolerated dose of 10
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mg and 20 mg, respectively. Treatment was then maintained without further up-titration until the primary analysis point at 52 weeks. Patients then entered the long-term double-blind extension period for a further 52 weeks of doubleblind treatment. During this period one single attempt at up-titration was allowed if HbA1c was >7%, but only if the patient had not already reached the maximum dose. During all study periods, downtitration was allowed in the event of recurrent hypoglycaemia. Patients with inadequate glycaemic control at maximum dose were discontinued from the study based upon time-dependent criteria; those during the 52-week double-blind treatment period were based upon FPG levels and have been previously reported [17]; those during the subsequent 52-week extension period were FPG >11.1 mmol/L and HbA1c ≥8%. As metformin therapy is contraindicated with renal impairment, patients were discontinued if calculated creatinine clearance using the Cockcroft-Gault equation [18] was 10 years, mean HbA1c was 7.72% [61 mmol/mol] with 10.7% of patients having a baseline HbA1c ≥9.0% [75 mmol/mol], mean FPG was 9.05 mmol/L, mean weight and body mass index (BMI) were 88.0 kg and 31.5 kg/m2, respectively, with 56.2% of patients presenting with a BMI ≥30 kg/m2.
Efficacy Durability of glycaemic control As previously reported, the HbA1c adjusted mean change from baseline with dapagliflozin was statistically non-inferior to glipizide at 52 weeks, with both treatments reducing HbA1c by −0.52% [−5.7 mmol/mol] [17]. The initial mean HbA1c reduction from baseline at 52 weeks was mostly sustained with dapagliflozin at 104 weeks (−0.32% [3.5 mmol/mol]; 95% CI: −0.42 [−4.6], −0.21 [−2.3]), but had attenuated with glipizide (−0.14% [1.5 mmol/mol]; 95% CI: −0.25 [−2.7], −0.03 [−0.3]) (Fig. 1A), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −0.18% [2.0 mmol/mol] (95% CI: −0.33 [−3.6], −0.03 [−0.3]; p=0.0211).
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The initial mean FPG reduction from baseline at the end of the titration period at 18 weeks (−1.12 mmol/L with dapagliflozin and −1.59 mmol/L with glipizide) was sustained with dapagliflozin at 104 (−1.12 mmol/L; 95% CI:−1.32, −0.92), but had attenuated with glipizide (−0.68 mmol/L; 95%
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CI:−0.89, −0.47) (Fig. 1B), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −0.44 mmol/L (95% CI: −0.73, −0.15; p=0.0030). Fewer patients were down-titrated or were discontinued due to inadequate glycaemic control with dapagliflozin compared with glipizide treatment (Table 1). Mean dose levels at the end of the 18week titration period for dapagliflozin and glipizide were 9.2 mg and 16.4 mg, respectively. Corresponding values at 104 weeks were 9.2 mg and 15.9 mg, respectively. The CoF slopes for dapagliflozin were significantly lower compared with glipizide, irrespective of which glycaemic variable (HbA1c or FPG) or analysis set was employed (Figs. 1C and 1D, Supplementary Table A1). Using the full analysis set, CoF for HbA1c from 18-104 weeks showed a rise of 0.13%/year [1.4 mmol/mol/year] (95% CI: 0.06 [0.7], 0.20 [2.2]) with dapagliflozin and a rise of 0.59%/year [6.4 mmol/mol/year] (95% CI: 0.48 [ 5.2], 0.71 [7.8]) with glipizide, resulting in a dapagliflozin vs glipizide difference of −0.46%/year [−5.0 mmol/mol/year] (95%CI: −0.60 [−6.6], −0.33 [−3.6]; p=0.0001). Corresponding values for FPG were 0.28 mmol/L/year (95% CI: 0.10, 0.46), 0.77 mmol/L/year (95% CI: 0.50, 1.04), and −0.48 mmol/L/year (95% CI: −0.81, −0.16; p=0.0033), respectively. Using the completers analysis set, CoF slopes for HbA1c and FPG were smaller in magnitude for both treatments, giving dapagliflozin CoF 18-52 week slopes that were not significantly different from zero (Figs. 1C and 1D). Comparisons of CoF slopes for HbA1c between 18-52 and 52-104 weeks, showed significant dapagliflozin versus glipizide differences for both time periods, irrespective of which analysis set was employed (Supplementary Table A1). The post hoc CoF sensitivity analysis of completers who were also not down-titrated produced very similar results to the CoF analysis of completers, irrespective of down-titration (Supplementary Table A1, and Supplementary Fig. A2).
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Maintenance of changes in weight The initial mean weight reduction from baseline at 52 weeks with dapagliflozin (−3.4 kg) and weight
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gain with glipizide (1.6 kg) remained relatively stable at 104 weeks with dapagliflozin (−3.7 kg; 95% CI: −4.2, −3.2) and glipizide (1.4 kg; 95% CI: 0.9, 1.8) (Fig. 1E), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −5.1 kg (95% CI: −5.7, −4.4). The proportion of patients achieving weight reduction ≥5% with dapagliflozin at 104 weeks was 23.8% (95% CI: 19.6, 27.9) and with glipizide was 2.8% (95% CI: 1.2, 4.4), resulting in a dapagliflozin versus glipizide difference at 104 weeks of 21.0 percentage points (95% CI: 16.5, 25.5).
Changes in blood pressure The initial mean seated systolic blood pressure reduction from baseline at 52 weeks with dapagliflozin (−3.8 mmHg) and increase in blood pressure with glipizide (0.9 mmHg) remained mostly stable at 104 weeks with dapagliflozin (−2.7 mmHg; 95% CI: −4.2, −1.2) and glipizide (1.2 mmHg; 95% CI: −0.4, 2.8) (Fig. 1F), resulting in a dapagliflozin versus glipizide difference at 104 weeks of −3.9 mmHg (95% CI: −6.1, −1.7).
Changes in urinary glucose excretion Dapagliflozin produced sustained increases in urinary glucose excretion over 104 weeks, as expected from its mechanism of action (Supplementary Fig. A3).
Safety and tolerability Hypoglycaemia The proportion of patients experiencing at least one hypoglycemic episode over 104 weeks was tenfold less with dapagliflozin, 17/406 (4.2%), than with glipizide, 187/408 (45.8%), with the majority of first episodes occurring during the first 18 weeks of treatment (Figure 2A).
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When analysed by total number of hypoglycemic events, 26 events were observed with dapagliflozin versus 843 events with glipizide over 104 weeks, with the majority of these events occurring during
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the first 18 weeks of treatment (Figure 2B). Among patients who experienced hypoglycaemia, the mean number and inter-individual variability of these events over 104 weeks was lower with dapagliflozin (mean, 1.5; standard deviation, 1.2; minimum, 1; maximum, 5) compared with glipizide (mean, 4.5; standard deviation, 5.7; minimum, 1; maximum, 38). No dapagliflozin-treated patients discontinued the study due to hypoglycaemia, whereas 7 glipizidetreated patients were discontinued for this reason (Tables 1 and 2).
Events suggestive of genital infection The proportion of patients experiencing events suggestive of genital infection over 104 weeks was 60/408 (14.8%) with dapagliflozin versus 12/408 (2.9%) with glipizide, with the majority of first episodes occurring during the first 52 weeks of treatment (Figure 2C). Genital infections were more common in women (Table 2). When analysed by total number of events suggestive of genital infection, 133 events were observed with dapagliflozin versus 14 events with glipizide over 104 weeks, with the majority of these events occurring during the first 52 weeks of treatment (Figure 2D). Of these events, 84.2% and 71.4% responded to initial standard treatment in the dapagliflozin and glipizide groups, respectively. Among patients who experienced events suggestive of genital infection over 104 weeks, the proportion of patients experiencing a single episode was 36/60 (60.0%) with dapagliflozin versus 10/12 (83.3%) with glipizide. The proportion of patients experiencing 2-3 events was 18/60 (30.0%) with dapagliflozin versus 2/12 (16.7%) with glipizide, and experiencing 4 or more events was 6/60 (10%) with dapagliflozin versus none with glipizide.
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Events suggestive of urinary tract infection The proportion of patients experiencing events suggestive of UTI over 104 weeks was 55/408 (13.5%)
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with dapagliflozin versus 37/408 (9.1%) with glipizide, with the majority of first episodes occurring during the first 52 weeks of treatment (Figure 2E). UTIs were more common in women (Table 2). When analysed by total number of events suggestive of UTI, 79 events were observed with dapagliflozin versus 50 events with glipizide over 104 weeks, with the majority of these events occurring during the first 52 weeks of treatment (Figure 2F). The rate of UTI from 52-104 weeks was comparable between the dapagliflozin (7.11/100 patient years; 95% CI: 4.28, 11.10) and glipizide (7.16/100 patient years; 95% CI: 4.24, 11.32) groups. Of these events, 89.7% and 84.2% responded to initial standard treatment, and 39.2% and 28.0% had a positive urine culture, in the dapagliflozin and glipizide groups, respectively. Among patients who experienced events suggestive of UTI over 104 weeks, the proportion of patients experiencing a single episode was 40/55 (72.7%) with dapagliflozin versus 27/37 (73.0%) with glipizide. The proportion of patients experiencing 2-3 events was 13/55 (23.6%) with dapagliflozin versus 10/27 (27.0%) with glipizide and experiencing 4-5 events was 2/55 (3.6%) with dapagliflozin versus none with glipizide. Kidney infections occurred in 3 patients treated with glipizide (2 pyelonephritis, 1 pyelocystitis/pyelonephritis) and in none treated with dapagliflozin.
General adverse event summary AEs and serious AEs (SAEs) were balanced across treatment groups (Table 1). SAEs considered related to study treatments were reported in 8 patients in the dapagliflozin group (complex ventricular arrhythmia, myocardial ischemia, decreased calculated creatinine clearance, epigastric pain, prostate cancer, pancreatic carcinoma, pulmonary embolism, and worsening of coronary artery disease) and in 7 patients in the glipizide group (3 SAEs of hypoglycaemia and one each of pyelonephritis, coronary artery occlusion, aortic aneurysm, bladder calculus).
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No deaths were reported in patients receiving dapagliflozin. Four deaths were reported in the group receiving glipizide due to mesenteric infarction, sudden death at home without autopsy, acute
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myocardial infarction, and road traffic accident. A total of 7 (3 prostate, 1 breast, 1 gastric and 2 pancreatic) and 3 (1 prostate, 1 skin, 1 lung) malignancies occurred during the 104 week study period in the dapagliflozin and glipizide groups, respectively (Table 2 and Supplementary Table A2).
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DISCUSSION Glycaemic durability over a 2-year period was significantly better with dapagliflozin compared with
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glipizide as demonstrated by Coefficient of Failure (CoF) slopes indicating a lower rate of HbA1c rise with dapagliflozin therapy. However, differential rates of discontinuation due to lack of glycaemic control or of down-titration or discontinuation due to hypoglycaemia, which were all higher in the glipizide arm, could partially explain the observed differences in CoF between the dapagliflozin and glipizide when estimated using the full analysis set only. Against this possibility, HbA1c in patients who completed the study and who were not down-titrated also showed an upward drift in HbA1c after the end of the titration period with glipizide, whereas HbA1c remained stable with dapagliflozin (Supplementary Fig. A2). Moreover, CoF with dapagliflozin using this latter analysis showed no significant rise in HbA1c over 2 years, whereas the rise in HbA1c remained significant with glipizide (Supplementary Table A1). In addition, up-titration during the long-term double-blind extension period, which occurred rarely but nevertheless more frequently with glipizide (Table 1), would have been expected to have produced CoF values more favourable to glipizide treatment, which was not the case. Taken together, these findings would suggest that, although the initial HbA1c drop was less with dapagliflozin compared with glipizide, long-term durability was greater with dapagliflozin treatment. Dapagliflozin demonstrated a low propensity to cause hypoglycaemia; the proportion of patients with episodes was 10-fold less with dapagliflozin compared with glipizide. For both treatments, hypoglycaemia was less frequent during the second year compared with the first year. However, this finding may have been influenced by rising HbA1c in the second year and/or poor patient recollection secondary to the increased time interval between study visits during the second year. It is noteworthy that among dapagliflozin-treated patients who had hypoglycemic episodes, the variability was low (a maximum of 5 episodes in any one patient), whereas among the higher number of glipizide-treated patients who had hypoglycemic episodes, variability was high (a maximum of 38 episodes in any one patient). This high number of episodes in a proportion of glipizide-treated patients was disturbing, as is reflected by the finding that 7 patients discontinued glipizide due to hypoglycaemia whereas none discontinued for this reason with dapagliflozin treatment (Table 2).
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The long-term glycaemic durability of dapagliflozin therapy (Fig. 1A-1D) and low rate of hypoglycaemia are likely to result from sustained urinary glucose excretion (Supplementary Fig. A3), which is neither influenced by changes in beta-cell secretory activity nor by changes in insulin
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sensitivity over time, whereas the lack of durability with glipizide is likely to have resulted from its dependence upon beta-cell function. In addition, persistent weight loss (Fig. 1E) and systolic blood pressure reduction (Fig. 1F) are likely to result from the urinary caloric loss and diuresis induced by dapagliflozin, respectively. These latter effects could indicate that dapagliflozin may potentially exert a beneficial effect on cardiovascular risk, as suggested by a meta-analysis of 14 dapagliflozin clinical trials of up to 2 years duration in which the hazard ratio for a composite endpoint of cardiovascular death, myocardial infarction, stroke or hospitalization for unstable angina was 0.82 (95% CI: 0.58, 1.15) [21]. However, full evaluation of the potential cardiovascular benefit/safety of dapagliflozin must await the outcome of the recently initiated DECLARE outcomes trial. Current treatment guidelines recommend the addition of a sulfonylurea, a thiazolidinedione, a dipeptidyl-peptidase IV (DPP-4) inhibitor, a glucagon-like peptide 1 (GLP-1) agonist, or insulin (in no particular preferential order) when metformin monotherapy fails [2]. Data directly comparing measures of glycaemic durability between sulfonylurea therapy and other oral glucose-lowering agents has demonstrated lower rates of HbA1c rise with pioglitazone [22], acarbose [22], and the DPP-4 inhibitors, saxagliptin [23], sitagliptin [24] and vildagliptin [25]. In the current report, glycaemic durability with dapagliflozin assessed over 2 years (CoF: HbA1c increase of 0.05%/year, completers analysis set) was significantly better than with glipizide (CoF: HbA1c increase of 0.28%/year, completers analysis set) and compares favourably with equivalent published data on per-protocol CoF slopes for saxagliptin showing an HbA1c increase of 0.05%/year [23] and for sitagliptin of 0.16%/year [24] assessed over 1 and 2-year periods, respectively. In addition, the dapagliflozin CoF HbA1c increase of 0.13%/year (full analysis set) compares favourably with recently published data on canagliflozin of a CoF HBA1c increase of 0.16%/year (modified intention-to-treat) over 2 years [26].The hypoglycaemia rate with dapagliflozin (4.2%) was comparable with published data on DPP-4 inhibitors (2.3-5%) [23-25], and much lower than with
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sulfonylureas (18.2-36.3%; 45.8%) [23,24,25;this report]. Weight loss with dapagliflozin was greater (3.7 kg) than in published data on DPP-4 inhibitors (0.3-1.6 kg) [23-25], whereas sulfonylureas produced weight gain (0.7-1.2 kg; 1.4 kg) [23,24,25;this report]. These data suggest that dapagliflozin
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can be considered a valuable alternative to sulfonylureas as an add-on therapy when metformin monotherapy fails to maintain glycaemic control. The lack of durable glycaemic efficacy, weight gain and hypoglycemic risk associated with sulfonylurea therapy, may explain why sulfonylureas are being used less today than in previous decades [27]. However, their low generic cost, together with trial data attesting some long-term benefits [28,29], contributes to their ongoing use despite increasing emphasis on the adverse event profile of sulfonylureas noted in guidelines [2,30]. As has been noted with the SGLT2-inhibitor class [15,17,31-38], events suggestive of genital infections and of UTIs, which included non-specific symptoms as well as clinically diagnosed infections, were more frequent with dapagliflozin compared with glipizide and were more commonly reported in women. Most of these infections were single episodes, most responded to routine management, and rarely led to study discontinuation. The rate of reported infection was lower in the second year of treatment, suggesting that adaptation to dapagliflozin exposure could occur, although poor patient recollection secondary to the increased time interval between study visits during the second year might explain this finding. Given that discontinuations due to infections were rare, the removal of patients at high risk of infection is an unlikely explanation for the reduced rate of infection in the second year. During the dapagliflozin clinical trial program, the overall proportion of patients with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.47%) and placebo/comparator (1.35%). Regarding differing tumours, the relative risk associated with dapagliflozin versus placebo/comparator was >1 for some tumours (bladder, prostate, breast) and
