Dapagliflozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin
A randomized, 52-week, double-blind, active-controlled noninferiority trial
OBJECTIVE Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy.
RESEARCH DESIGN AND METHODS This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤10 or ≤20 mg/day, respectively.
RESULTS The primary end point, adjusted mean HbA1c reduction with dapagliflozin (−0.52%) compared with glipizide (−0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (−3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation.
CONCLUSIONS Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.
Metformin is recommended as the initial oral antidiabetic drug (OAD) therapy for patients with type 2 diabetes (1–5), but the progressive nature of type 2 diabetes often requires treatment intensification to maintain glycemic control (6). A sulfonylurea or insulin is commonly added to metformin as a second step (1–5). Although initially effective, sulfonylurea treatment is associated with poor glycemic durability (6), weight gain, and hypoglycemia (7,8).
Dapagliflozin is the first in a novel class of glucose-lowering medications, the selective sodium-glucose cotransporter 2 (SGLT2) inhibitors (9). These agents reduce glucose reabsorption from the proximal tubule of the kidney, leading to increased urinary glucose excretion with resulting net caloric loss (10). This effect depends on baseline glycemic control and the renal filtration rate but is independent of insulin. Consequently, reduction in plasma glucose with dapagliflozin reduces the glucose load filtered by the kidney and limits further glucose excretion, suggesting that dapagliflozin may possess a low intrinsic propensity for hypoglycemia (11). Dapagliflozin might thus provide an alternative to existing add-on therapies by improving glycemic control without associated weight gain or hypoglycemic risk.
Recent placebo-controlled clinical trials of 24-weeks’ duration have shown promise for dapagliflozin as monotherapy in patients with type 2 diabetes (12) and as add-on therapy in patients inadequately controlled with metformin (13), but longer-term head-to-head trials comparing dapagliflozin with established therapies are required. The current study directly tested the efficacy, safety, and tolerability of dapagliflozin against glipizide during a treatment period of 52 weeks in patients with type 2 diabetes inadequately controlled by metformin monotherapy.
RESEARCH DESIGN AND METHODS
This was a 52-week randomized, double-blind, parallel-group, active-controlled, phase III, noninferiority trial with a 156-week extension period conducted from 31 March 2008 and ongoing at 95 sites in 10 countries: Argentina, 17 centers; France, 7; Germany, 16; U.K., 12; Italy, 3; Mexico, 4; the Netherlands, 10; South Africa, 10; Spain, 6; and Sweden, 10. Patient disposition is shown in Supplementary Fig. A1. 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 centers, and is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent before entering the study. Data from the 52-week double-blind treatment period are presented here.
This study enrolled men and women aged ≥18 years with inadequately controlled type 2 diabetes (HbA1c >6.5 and ≤10%) while receiving metformin or metformin and one other OAD administered up to half-maximal dose for at least 8 weeks before enrollment. A maximum of 25% of randomized patients had a baseline HbA1c <7%. Further criteria included a fasting plasma glucose (FPG) ≤15 mmol/L and C-peptide concentration of ≥0.33 nmol/L. Exclusion criteria are listed in the Supplementary Data.
Treatments and interventions
Eligible patients receiving metformin monotherapy at a stable dose of <1,500 mg/day or at a variable dose, or combined with another OAD, entered an 8-week stabilization period during which other OADs were discontinued and the metformin dose was stabilized to 1,500–2,500 mg/day in all patients. Patients who were already receiving a stable dose of metformin monotherapy (1,500–2,500 mg/day) for at least 8 weeks before enrollment skipped the dose-stabilization period (Supplementary Table A1). Once patients were stabilized, no further changes in the metformin dose were allowed. All patients received dietary and lifestyle advice commencing from the start of the dose-stabilization period.
After a 2-week, single-blind, placebo lead-in period, patients were randomized in a 1:1 ratio to receive double-blind treatment with dapagliflozin or glipizide. All patients commenced treatment at dosage level 1, which was dapagliflozin at 2.5 mg or glipizide at 5 mg. During an 18-week period and at 21-day intervals, patients were up-titrated to the next dosage level if FPG was ≥6.1 mmol/L. Level 2 was dapagliflozin at 5 mg or glipizide at 10 mg, and level 3 was dapagliflozin at 10 mg or glipizide at 20 mg. Up-titration continued until the maximum tolerable dose level was reached. A 20-mg limit for glipizide was chosen because the glycemic benefits of sulfonylureas are virtually complete at half-maximal doses, and higher doses are generally not recommended (2).
After the 18-week titration period, patients entered a 34-week maintenance period, during which no further up-titration was allowed. However, patients could be down-titrated to the preceding level or potentially down to level 0 (placebo for both arms) in the event of recurrent hypoglycemia.
Patients with inadequate glycemic control during the 52-week double-blind treatment period were discontinued according to time-specific criteria. After having received a maximum titrated or tolerated dose for at least 2 weeks, patients were discontinued if their FPG was 1) >15 mmol/L at weeks 3, 6, or 9; 2) >13.3 mmol/L at weeks 12, 15, or 18; 3) >12.2 mmol/L at weeks 26 or 34; or 4) >11.1 mmol/L at week 42. Because metformin therapy is contraindicated with renal impairment, patients were also discontinued at any point in the study if the calculated creatinine clearance using the Cockcroft-Gault equation (14) was <60 mL/min.
Allocation concealment and blinding
Patients were randomized sequentially at study level according to a predefined computer-generated randomization scheme provided by AstraZeneca. Allocation of study treatments was performed via an Interactive Web Response System in balanced block sizes of 4 to ensure approximate balance among treatment groups. Blinding of patients and investigators to study treatment was achieved using a double-dummy technique. Metformin was administered as an open-label treatment throughout the study.
End points and safety assessments
The predefined primary end point was absolute change in HbA1c from baseline to week 52. Key secondary end points were 1) absolute change in total body weight (TBW) from baseline to week 52; 2) proportion of patients reporting at least one episode of hypoglycemia (“major,” “minor,” or “other,” episode) during the 52-week double-blind treatment period; and 3) the proportion of patients achieving a TBW decrease ≥5% from baseline to week 52. Major hypoglycemia was defined as a symptomatic episode requiring external assistance due to severely impaired consciousness or behavior, with capillary or plasma glucose levels of 54 mg/dL (<3.0 mmol/L) and recovery after glucose or glucagon administration. Minor hypoglycemia was defined as a symptomatic episode with capillary or plasma glucose levels of 63 mg/dL (<3.5 mmol/L), irrespective of the need for external assistance, or an asymptomatic episode with capillary or plasma glucose levels of 63 mg/dL (<3.5 mmol/L) that did not qualify as a major episode. Other hypoglycemia was defined as an episode with symptoms suggestive of hypoglycemia but without measurement confirmation.
A number of exploratory end points were assessed, including change from baseline to week 52 for body weight in patients with a baseline BMI ≥30 kg/m2 and in those with baseline BMI ≥27 kg/m2, waist circumference, change in HbA1c in patients with an HbA1c of ≥7% at baseline, and FPG. The proportions of patients with HbA1c <7% at week 52 in patients with baseline HbA1c ≥7% and proportions of patients with HbA1c ≤6.5% at week 52 were also assessed. Absolute changes from baseline to week 52 for seated systolic and diastolic blood pressure, and percent changes from baseline to week 52 for total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and free fatty acids were assessed.
Safety and tolerability was assessed by collating data on adverse events (AEs) using the Medical Dictionary for Regulatory Activities (MedDRA version 12.1), hypoglycemic events, laboratory tests, calculated creatinine clearance, urinary glucose/creatinine ratio, electrocardiographic and physical examinations, and vital signs. In addition, patients were actively questioned at each study visit to assess signs, symptoms, and reports suggestive of genital infections and urinary tract infections (UTIs). These responses, and those obtained spontaneously, were categorized in the database using a predefined list of MedDRA terms suggestive of genital infections and UTIs.
A hierarchic closed-testing procedure was used to control the type I error rate across the primary and key secondary end points at the 0.05 level (two-sided). Thus, if noninferiority was established for the primary end point at a one-sided 0.025 significance level, then key secondary end point testing for superiority could proceed in the sequence described previously. If the first key secondary end point was significant at a two-sided 0.05 significance level, then the second secondary end point could be evaluated, and so forth.
The primary and continuous key secondary and exploratory end points were evaluated using ANCOVA, with treatment as the fixed effect and baseline value as the covariate, to derive a least squares estimate of the treatment difference in mean change with corresponding two-sided 95% CI. Proportions were analyzed using logistic regression with adjustment for baseline values as described by Zhang et al. (15). Statistical noninferiority of dapagliflozin versus glipizide was established if the upper limit of the 95% CI for the treatment difference in mean HbA1c change from baseline to week 52 was <0.35% (noninferiority margin). For graphic presentation of HbA1c and TBW over the 52-week treatment period, the change from baseline (last observation carried forward [LOCF]) was analyzed at each interval using ANCOVA with treatment as the fixed effect and baseline value as the covariate. The Kaplan-Meier method was used to analyze time to onset of patient discontinuation because of poor glycemic control.
Two analysis sets were defined: the safety analysis set, consisting of all patients who received one or more doses of the investigational product, and the full analysis set, consisting of all randomized patients who received one or more doses of the investigational product and who had a nonmissing baseline and one or more postbaseline efficacy value for one or more efficacy variable. Primary, key secondary, and exploratory end points were analyzed using the full analysis set. Missing values at week 52 were replaced using the LOCF method.
Prespecified safety analyses, including events suggestive of genital infection and UTI, were performed using descriptive statistics for the safety analysis set. A post hoc exploratory analysis of risk differences for the proportions of patients reporting events suggestive of genital infections and of UTIs were performed using Fisher exact tests. Sample size calculations are available in the Supplementary Data.
The full analysis set comprised 801 patients (dapagliflozin: n = 400; glipizide: n = 401) and the safety analysis set, 814 patients (dapagliflozin: n = 406; glipizide: n = 408). Overall, 77.9% of randomized patients completed the study. The commonest reasons for discontinuation were withdrawal of consent, AEs, and no longer meeting study criteria (Supplementary Fig. A1). Efficacy analyses used LOCF and the full analysis set, which included 98.2% of randomized patients; therefore, almost all of the discontinued patients were included in these analyses. Demographic and baseline characteristics were balanced across treatment groups (Supplementary Table A2).
At the end of the titration period, 353 patients (86.9%) randomized to receive dapagliflozin were receiving the maximum dose of 10 mg, whereas 296 patients (72.5%) randomized to receive glipizide were receiving the maximum dose of 20 mg, resulting in mean doses of 9.2 mg for dapagliflozin and 16.4 mg for glipizide (Supplementary Table A3). During the titration period, seven patients receiving glipizide versus none receiving dapagliflozin were down-titrated to receive no study treatment. Overall, 2.7% of patients receiving dapagliflozin versus 15.9% of those receiving glipizide were down-titrated during the titration or maintenance periods.
Primary end point
The HbA1c adjusted mean change from baseline at week 52 for dapagliflozin was −0.52 (95% CI −0.60 to −0.44) vs. −0.52 (−0.60 to −0.44) for glipizide; hence, the dapagliflozin HbA1c mean difference from glipizide at week 52 was 0.00 (−0.11 to 0.11). Thus, HbA1c change with dapagliflozin was statistically noninferior to that with glipizide at week 52.
Although the initial drop in HbA1c during the titration period with glipizide was greater than that observed with dapagliflozin, efficacy for glipizide waned during the maintenance period but remained stable for dapagliflozin. This resulted in equivalent efficacy at week 52 (Fig. 1A). During the maintenance period, 5.1% of patients in the glipizide group were down-titrated versus 0.5% in the dapagliflozin group (Supplementary Table A3).
Secondary end points
Dapagliflozin produced weight loss, whereas glipizide led to weight gain, resulting in an absolute mean difference of 4.65 kg (P < 0.0001) at week 52 (Fig. 1B). Dapagliflozin showed a significantly greater adjusted proportion of patients with a body weight reduction of ≥5% at week 52 (Fig. 2B).
The adjusted proportion of patients experiencing at least one hypoglycemic episode by week 52 was more than 10-fold lower with dapagliflozin than with glipizide (Fig. 2A).
The proportion of patients discontinuing due to inadequate glycemic control by week 52 was 0.2% in the dapagliflozin group versus 3.6% in glipizide group (difference −3.6%; 95% CI −5.3 to −1.5). Time to discontinuation was also prolonged with dapagliflozin versus glipizide (Fig. 2C).
Exploratory end points
Dapagliflozin reduced seated systolic and diastolic blood pressure, and increased HDL cholesterol (Supplementary Fig. A2). Dapagliflozin reduced body weight in patients with BMI of >27 or >30 kg/m2 and produced glycemic changes equivalent to glipizide, as expected from the noninferior HbA1c result, with the exception of the proportion of patients with HbA1c ≤6.5% at week 52, which favored glipizide (Supplementary Table A4).
Safety and tolerability
AEs and serious AEs (SAEs) leading to study discontinuation were balanced across treatment groups (Table 1). SAEs considered related to study treatments were reported in six patients in the dapagliflozin group (complex ventricular arrhythmia, decreased calculated creatinine clearance, epigastric pain, prostate cancer, pulmonary embolism, and worsening of coronary artery disease) and in four patients in the glipizide group (hypoglycemia in three and pyelonephritis in one). No deaths were reported in patients receiving dapagliflozin. Three deaths were reported in the group receiving glipizide, comprising mesenteric infarction, sudden death at home without autopsy, and acute myocardial infarction.
AEs led to study discontinuation in 37 patients receiving dapagliflozin (9.1%) versus 24 receiving glipizide (5.9%), which was mainly accounted for by an excess of patients who were withdrawn because of decreased calculated creatinine clearance with dapagliflozin (n = 13) versus glipizide (n = 6; Table 1). Creatinine clearance was calculated using the Cockcroft-Gault equation (14), with current body weight values at all visits. A post hoc estimation using baseline weight at each study visit showed no change in mean calculated creatinine clearance (Supplementary Table A5). One patient receiving dapagliflozin developed acute hepatitis and was later diagnosed with drug-induced acute hepatitis as well as probable autoimmune hepatitis. This patient’s liver function test values decreased 10 days after suspension of dapagliflozin and normalized 6 months later in response to immunosuppressive treatment.
Prespecified safety analyses of special interest.
Fewer hypoglycemic events were reported in patients treated with dapagliflozin compared with glipizide (Table 1), and results were comparable with the efficacy analysis of adjusted proportions of patients experiencing hypoglycemia (Fig. 2A). No patients discontinued dapagliflozin treatment as a result of a hypoglycemic event compared with six patients receiving glipizide. Three patients taking glipizide, but none taking dapagliflozin, reported major hypoglycemic episodes (symptomatic patients requiring external assistance and with a plasma glucose <3.0 mmol/L).
Higher proportions of patients receiving dapagliflozin reported events suggestive of genital infections or lower UTIs compared with glipizide. About half of the genital events were recurrent, whereas most of the lower UTIs were single episodes. Except for three patients, all events were reported as mild or moderate in intensity. Not all of these events could be confirmed by microbiologic culture, but they nevertheless responded to routine management and rarely led to study discontinuation (Table 1). Two cases of pyelonephritis were reported in the glipizide group, whereas none were reported in the dapagliflozin group (Table 1).
One report of renal failure (creatinine clearance 106, 95, and 52 mL/min on day −22, 1, and 43, respectively) was considered related to dapagliflozin and resulted in treatment discontinuation. Although this AE was assessed as mild in intensity, nonserious by the investigators, and no treatment was administered, no end date for the AE was documented.
Six patients receiving dapagliflozin and three receiving glipizide experienced AEs of hypotension, dehydration, or hypovolemia (Table 1). None were assessed as serious by the investigators, and no patient discontinued treatment as a consequence.
Laboratory values and vital signs.
Dapagliflozin dramatically increased urinary glucose excretion and the urinary glucose/creatinine ratio (Supplementary Table A5), as expected from its mechanism of action. Dapagliflozin-induced glucose excretion remained elevated and constant from week 12 to 52, showing no sign of diminished activity during this period (Supplementary Fig. A3). Changes from baseline at week 52 with dapagliflozin treatment included increased mean values for hematocrit, blood urea nitrogen, magnesium, and phosphorus, and decreased mean values for aspartate aminotransferase, alanine aminotransferase, and serum uric acid. No changes in bilirubin, heart rate, or in the proportions of patients experiencing orthostatic hypotension were noted (Supplementary Table A5).
In the context of a dose-titration scheme designed to optimize efficacy and minimize hypoglycemic episodes with glipizide, this head-to-head comparison study demonstrated that the novel SGLT2 inhibitor dapagliflozin produced a long-term HbA1c mean reduction at 52 weeks that was numerically identical and statistically noninferior to the sulfonylurea glipizide in patients poorly controlled with metformin monotherapy. This comparable long-term efficacy of dapagliflozin with a sulfonylurea, considered potent glucose-lowering agents (2), was achieved with >10-fold fewer hypoglycemic episodes along with sustained weight loss. In contrast, weight increased and hypoglycemic episodes were more frequent with glipizide.
The pattern of HbA1c change over time was substantially different between dapagliflozin and glipizide treatment (Fig. 1A). The pattern with glipizide—rapid initial response, followed by gradual increase—is typical of that observed with sulfonylureas (6,16). In contrast, dapagliflozin response was initially smaller during titration but thereafter was sustained during the maintenance period such that it was identical to glipizide response at 52 weeks. It is interesting to speculate whether the durability of HbA1c control with dapagliflozin will outlast that of glipizide during longer-term follow-up of these patients. In this population with a relatively low baseline mean HbA1c (∼7.7%), clinically meaningful reductions of >0.5% were achieved by both agents. A higher baseline HbA1c, as observed in other clinical efficacy studies of antidiabetic agents, generally predicts larger drops in response to treatment, whichever agent is tested (17,18).
Weight loss with dapagliflozin was progressive during the first 6 months and stabilized during the latter half of the study. This may have resulted from glucosuria-induced fat loss, fluid loss associated with osmotic diuresis, or a combination of both. Studies of body composition are underway to assess the relative contributions of fat and fluid loss to the changes in TBW observed with dapagliflozin.
Dapagliflozin reduced blood pressure. The mechanism for this effect is unclear but may involve osmotic diuresis or sodium loss. Although modest rises in hematocrit and blood urea nitrogen occurred, no meaningful changes were noted in electrolytes, serum creatinine, heart rate, or proportions of patients experiencing orthostatic hypotension to indicate dehydration. The estimated glomerular filtration rate and concentrations of cystatin-C did not show meaningful changes. In addition, AEs of renal impairment or failure—excluding those of decrease in creatinine clearance calculated using current body weight values at each study visit—were not over-represented with dapagliflozin. Taken together, these data suggest that dapagliflozin treatment was not associated with clinically relevant dehydration or impairment in kidney function.
Patients with type 2 diabetes are at higher risk of fungal genital infections and UTIs compared with the general population (19). Dapagliflozin-treated patients, especially women, reported an increase in events suggestive of genital infections and lower UTIs compared with glipizide-treated patients. For conservative pharmacovigilance purposes with this first-in-class agent, events suggestive of genital infection and UTI were reported spontaneously and in response to questions proactively posed to patients that were related to the signs and symptoms of these infections. Not all of these suggestive events could be confirmed as infections (Table 1). Variable reports of these events have been noted in previous studies with dapagliflozin (13,18,20,21); hence, further analyses using pooled data are required to better evaluate potential risk factors for genital and UTIs with SGLT2 inhibitors such as dapagliflozin.
In conclusion, this head-to-head comparison of dapagliflozin versus glipizide added to metformin in type 2 diabetic patients inadequately controlled with metformin monotherapy demonstrated similar glycemic efficacy at 52 weeks but markedly divergent effects on weight and hypoglycemia. Whereas glipizide treatment led to weight gain and more hypoglycemic episodes, dapagliflozin produced significant weight loss and significantly fewer hypoglycemic episodes. Dapagliflozin treatment was generally safe and well tolerated, but events suggestive of genital and lower UTIs were observed more frequently in this study. Dapagliflozin is a potential valuable alternative to sulfonylureas as add-on therapy when metformin monotherapy fails to maintain adequate glycemic control.
This study was supported by AstraZeneca and Bristol-Myers Squibb. M.A.N. has been a member of advisory boards or has consulted with AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Hoffman-La Roche, Menarini/Berlin-Chemie, Merck Sharp & Dohme, Novo Nordisk, and Versatis. He has received grant support from Eli Lilly & Co., Menarini/Berlin-Chemie, Merck Sharp & Dohme, Novartis Pharmaceuticals, and Ypsomed. He has served on the speakers’ bureaus of AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Hoffman-La Roche, Menarini/Berlin-Chemie, Merck Sharp & Dohme, and Novo Nordisk. S.D.P. has been a member of advisory boards with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, Roche Pharmaceuticals, sanofi-aventis, and Takeda Pharmaceuticals. He has received grant support from Merck Sharp & Dohme, sanofi-aventis, and Takeda Pharmaceuticals. He has served on the speakers’ bureaus of GlaxoSmithKline and sanofi-aventis. J.J.M. has received speaker or advisory board fees from AstraZeneca, Menarini/Berlin-Chemie, Bristol-Myers Squibb, Eli Lilly & Co., Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, Roche Pharmaceuticals, and sanofi-aventis. He has received research support from Eli Lilly & Co., Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, and sanofi-aventis. K.R. and S.J.P. are full-time employees of AstraZeneca Pharmaceuticals. M.E. is an employee of ClinResearch, which is contracted to support data analysis for AstraZeneca. No other potential conflicts of interest relevant to this article were reported.
M.A.N., S.D.P., and S.D.-G. acquired data, analyzed and interpreted data, and wrote and revised the article. J.J.M. and S.J.P. contributed to the study concept and design, analyzed and interpreted data, and wrote and revised the article. K.R. supervised the study, analyzed and interpreted data, and wrote and revised the article. M.E. contributed to the study concept and design, contributed to statistical verification of data, analyzed and interpreted data, and wrote and revised the article.
Parts of this study were presented in abstract form at the 46th Annual Meeting of the European Association for the Study of Diabetes, Stockholm, Sweden, 20–24 September 2010, and at the 71st Scientific Sessions of the American Diabetes Association, San Diego, California, 24–28 June 2011.
The authors thank Julian Martins of inScience Communications (a Wolters Kluwer business) for medical writing and editorial assistance. This assistance was funded by AstraZeneca and Bristol-Myers Squibb.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-0606/-/DC1.
A complete list of study investigators can be found in the Supplementary Data online.
- Received April 11, 2011.
- Accepted June 27, 2011.
- © 2011 by the American Diabetes Association.
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