Visual Abstract
Abstract
Background Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.
Methods Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up).
Results Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (−0.77; 95% confidence interval, −0.83 to −0.71; placebo: 0.01; 95% confidence interval, −0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: −1.46; 95% confidence interval, −1.74 to −1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo −0.02; 95% confidence interval, −0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk.
Conclusions The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.
The prevalence of diabetic kidney disease continues to rise and is predicted to affect 200 million people around the world by 2040.1 Although improved glycemic control and widespread use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have contributed to an improved prognosis for patients with diabetic kidney disease, their renal and cardiovascular risks remain high, underscoring the need for novel therapeutic interventions.
Empagliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, has been shown to reduce hyperglycemia, BP, and body weight in patients with type 2 diabetes.2,3 In the EMPA-REG OUTCOME Trial, empagliflozin markedly decreased the risk of clinically important cardiovascular events (in particular, the risk of cardiovascular death), and in further hypothesis-generating analyses, it delayed the progression of CKD in people with type 2 diabetes and established cardiovascular disease.4,5
The beneficial kidney effects associated with empagliflozin are thought to be mediated by various mechanisms, including restoration of tubuloglomerular feedback leading to a reduction in intraglomerular pressure and hyperfiltration.6 Both conditions are considered core components of the pathophysiology contributing to progression of diabetic as well as nondiabetic CKD.7 In a previous mechanistic study comprising individuals with type 1 diabetes, empagliflozin was shown to reduce glomerular hyperfiltration, likely by reducing intraglomerular pressure.8,9 Reductions in intraglomerular pressure, as shown by agents blocking the renin-angiotensin system, are frequently accompanied by a hemodynamic acute decrease in GFR, which is reversible after treatment cessation. Previous studies in patients with type 2 diabetes at various stages of CKD have shown that empagliflozin decreased eGFR by approximately 2–4 ml/min per 1.73 m2 during the first weeks of treatment followed by a return to baseline values after treatment cessation.10,11
The EMPA-REG OUTCOME Trial yields a large, well characterized, and prospectively followed cohort. This provides an opportunity to more precisely understand the clinical effects of empagliflozin in patients with concomitant CKD12 as well as delineate differences in the rate of change in kidney function over time (i.e., eGFR slope) during the acute (treatment initiation), chronic maintenance, and post-treatment (follow-up) phases with empagliflozin in a range of patients with type 2 diabetes, and a previous report has provided the first results.5 In this manuscript, we provide additional in-depth assessments of the prespecified analysis of eGFR slopes from the EMPA-REG OUTCOME Trial. We aimed to specifically investigate the consistency and clinical relevance of the effect of empagliflozin on acute changes in eGFR after treatment initiation, eGFR slopes during chronic maintenance treatment, and eGFR changes after study drug discontinuation. These analyses were performed in the overall trial population and then, within specific subgroups of individuals at higher risk of progressive CKD.
Methods
Design of the EMPA-REG OUTCOME Trial
As described in detail previously,4,13 the EMPA-REG OUTCOME Trial (ClinicalTrials.gov identifier: NCT01131676) was a double-blind, placebo-controlled, multinational trial in which adults with type 2 diabetes, glycated hemoglobin A1c (HbA1c) ≥7%, and established cardiovascular disease were randomized in a 1:1:1 ratio to empagliflozin 10 mg, empagliflozin 25 mg, or placebo, all added to background standard of care. Background glucose-lowering therapy was to remain unchanged for the first 12 weeks, after which investigators were encouraged to adjust glucose-lowering therapy to achieve glycemic control according to local guidelines. Moreover, investigators were encouraged to treat other cardiovascular risk factors to the standard of care according to local guidelines.
Patients were required to have an eGFR of ≥30 ml/min per 1.73 m2 (on the basis of the Modification of Diet in Renal Disease study [MDRD] formula) at screening. Patients attended the clinic at the following prespecified study visits: screening; baseline; weeks 4, 12, 16, 28, 40, and 52; every 14 weeks until treatment stopped (due to either end of study or discontinuation of study drug); and a final visit approximately 30 days after treatment cessation.13 Serum creatinine and urinary albumin-to-creatinine ratio (UACR) were measured by a central laboratory using standardized procedures.14 Serum creatinine was used to calculate eGFR using the MDRD equation. The primary outcome of the trial was defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and results have been reported previously.4
Analyses
A mixed model for repeated measurements, which includes time points of the prescheduled measurements as fixed effects, was fitted to provide a descriptive presentation of the adjusted mean eGFR over time for empagliflozin and placebo groups. The model included “baseline HbA1c” and “baseline eGFR” as linear covariates and “geographic region,” “baseline body mass index,” “the last week that a patient could have had an eGFR measurement,” “treatment,” “visit,” “interaction between visit and treatment,” “interaction between the baseline HbA1c and visit,” and “interaction between the baseline eGFR and visit” as fixed effects. An unstructured covariance matrix was used to account for serial correlation.
For the slope analysis reported here, the main prespecified efficacy outcome was the average rate of change of eGFR per year during the trial period when patients received stable treatment with study drug (week 4 until treatment cessation; i.e., the chronic maintenance treatment period), and results are expressed as annual changes in eGFR. In addition, the average rate of change in eGFR per week in the first 4 weeks after starting treatment was assessed (i.e., treatment initiation period) as well as that in the 30 days after stopping treatment (i.e., post-treatment cessation period). Changes in eGFR per week or year, further referred to as eGFR slope, were obtained using random coefficient models. Assessment of eGFR slope in the overall population was a prespecified analysis of the trial; post hoc analyses were also conducted in relevant subgroups at higher risk for CKD progression defined by baseline eGFR, UACR, race, BP, age, and HbA1c levels. For the overall population, the models included the following factors: “treatment,” “baseline body mass index,” and “geographic region” as fixed classification effects and “baseline HbA1c,” “time,” and “interaction of treatment by time” as linear covariates. Intercepts and slopes over time were allowed to vary randomly between patients by including the patient and time as random effects. Histogram plots of fitted individual eGFR slopes were provided for each period by treatment. For the subgroup analysis, the models additionally included the fixed factor for the subgroup as well as terms for treatment by subgroup interaction and treatment by subgroup by time interaction. Because empagliflozin was previously shown to exert an acute hemodynamic effect, eGFR slopes were separately calculated for three prespecified study periods: treatment initiation effects from baseline to week 4, chronic maintenance treatment effects from week 4 to last value on treatment, and post-treatment effects from last value on treatment to follow-up (planned to be approximately 30 days after cessation of treatment). For the first two time periods, only on-treatment data before stopping the blinded study drug was used, because it was expected that eGFR would increase after empagliflozin treatment was stopped. For the chronic maintenance treatment period, a uniform treatment effect was defined by a consistent shift of the distribution of individual eGFR slopes for empagliflozin compared with the distribution of individual eGFR slopes for placebo.15 Thus, consistent changes across the population would be denoted by equally symmetric curves, such that the individual changes in eGFR are consistent in not only their directionality but also, their size. For the chronic maintenance treatment period, SDs of the empagliflozin and placebo arms were derived, and homogeneity was tested by the Levene test. These SDs reflect a combination of the variation in the true slopes and the variation in the estimated slopes relative to the true slopes. An additional sensitivity analysis for the chronic maintenance treatment period applied the random-intercept/random-coefficient model using log-transformed eGFR data. Significance was determined on the basis of an α-level of 0.05 without correction for multiple testing. Additional details of the eGFR slopes analyses are in Supplemental Material.
Data Sharing
The sponsor of the EMPA-REG OUTCOME Trial (Boehringer Ingelheim) is committed to responsible sharing of clinical study reports, related clinical documents, and patient-level clinical study data. Researchers are invited to submit inquiries via the Clinical Study Data Request website (https://www.clinicalstudydatarequest.com).
Results
Patient Disposition
A total of 7020 patients were randomized between September 2010 and April 2013 and received at least one dose of study drug (placebo: n=2333; empagliflozin 10 mg: n=2345; empagliflozin 25 mg: n=2342) at 590 sites in 42 countries. The median duration of treatment was 2.6 years, and the median observation time was 3.1 years. Overall, 97.0% of patients completed the study, and final vital status was available for 99.2%; 683, 555, and 542 patients treated with placebo, empagliflozin 10 mg, or empagliflozin 25 mg, respectively, prematurely discontinued trial medication (i.e., 25.4% of the total trial population), and reasons for premature discontinuation of study drug have been reported.4
Baseline Characteristics
At baseline, clinical characteristics and concomitant medications were similar between the placebo and empagliflozin groups as reported previously.4 Baseline eGFR measurements were available for the majority of patients (missing only for two patients in the empagliflozin 25 mg group). More than one quarter (n=1819; 25.9%) of the patients had eGFR<60 ml/min per 1.73 m2 at baseline (1249 [17.8%] with eGFR=45–59 ml/min per 1.73 m2 [CKD stage 3A]; 543 [7.7%] with eGFR=30–44 ml/min per 1.73 m2 [CKD stage 3B]), and 40.0% (n=2782) had prevalent albuminuria (microalbuminuria [UACR=30–300 mg/g]: 2013 [28.9%]; macroalbuminuria [UACR>300 mg/g]: 769 [11.0%]). Nearly one third (n=2250; 32.1%) had prevalent kidney disease defined as eGFR<60 ml/min per 1.73 m2 and/or macroalbuminuria. Overall, 95% of patients were taking antihypertensive therapies at baseline, most commonly ACE inhibitors or ARBs (80.7%), β-blockers (64.9%), and diuretics (43.2%).
Empagliflozin Is Associated with Consistent Shifts in Individual eGFR Slopes
Adjusted mean eGFR values over time for the pooled empagliflozin and placebo groups are shown in Figure 1 on the basis of a mixed model for repeated measurements. In the next step, we calculated the estimated individual patient slopes on the basis of prespecified random coefficient models to assess the distribution of individual eGFR slopes. As shown in Figure 2, the effect of empagliflozin was considered to show a consistent shift across the distribution of individual eGFR changes compared with the rate of individual eGFR changes in the placebo group, and this finding was evident during all three prespecified periods. Hence, compared with placebo treatment, the distribution of individual eGFR slopes in the pooled empagliflozin group shifted leftward during treatment initiation (baseline to week 4), indicating a reduction in mean eGFR, but thereafter, it shifted rightward during both chronic maintenance treatment (week 4 to last value on treatment) and follow-up (last value on treatment to follow-up), indicating a period of slower loss of kidney function followed by an increase in mean eGFR, respectively. The changes in mean eGFR during the chronic maintenance treatment period (i.e., the most clinically relevant period) are considered uniform, because the SDs in the placebo and empagliflozin arms were similar (1.51 versus 1.65 ml/min per 1.73 m2, respectively; ratio, 0.9169). Testing for homogeneity by the Levene test did not reveal evidence that the SDs of the two treatment arms were significantly different (P=0.06). Results from the sensitivity analysis using log eGFR provided similar results (SDs in placebo and empagliflozin arms: 0.029 versus 0.029 ml/min per 1.73 m2, respectively; ratio, 1.0266; Levene test P=0.71). In an additional sensitivity analysis, the distribution of individual eGFR slopes with the two doses of empagliflozin (10 and 25 mg) was considered to also reflect a consistent shift across all three prespecified study periods, confirming the overall consistency of the individual doses with the pooled analyses (Supplemental Figure 1).
eGFR over time was different between empagliflozin and placebo in the EMPA-REG OUTCOME Trial in type 2 diabetes mellitus patients. eGFR is according to Modification of Diet in Renal Disease formula. Prespecified mixed model repeated measures analysis in patients treated with one or more doses of study drug who had a baseline measurement and at least one postbaseline measurement. Measurements obtained during study drug intake were used in this analysis. SE, SEM.
Empagliflozin showed a uniform shift across the distribution of individual eGFR changes compared with placebo. Overall population, pooled empagliflozin groups. Distribution of individual eGFR slopes over three prespecified study periods. The shape and symmetry of the curves during chronic maintenance treatment (annual slope) reflect a uniform shift in individual eGFR changes with empagliflozin. Individual slopes represent the individual patient’s average change in eGFR (Modification of Diet in Renal Disease) per week (for initiation and cessation) and per year (for chronic maintenance treatment) for prespecified study periods assessed using random-intercept/random-coefficient models.
Empagliflozin Slows the Annual Decline in eGFR Assessed by Mean eGFR Slopes
Adjusted mean eGFR slopes over the three prespecified study periods are shown in Figure 3A. During the treatment initiation phase, the weekly mean adjusted eGFR significantly declined in the empagliflozin group compared with the placebo group (Figure 3B). Thereafter, the annual adjusted change in mean eGFR during the chronic maintenance treatment period was not further reduced in the empagliflozin group (+0.23 ml/min per year per 1.73 m2; 95% confidence interval, 0.05 to 0.40) and declined in the placebo group (−1.46 ml/min per year per 1.73 m2; 95% confidence interval, −1.74 to −1.17; P<0.001 for empagliflozin versus placebo) (Figure 3B). The study included a post-treatment follow-up period, with eGFR measurements performed at approximately 30 days after the end of study drug intake. During this phase, the weekly adjusted mean eGFR change significantly increased in the empagliflozin group and overall returned toward mean baseline eGFR levels, with little change seen in the placebo group (Figure 3B). Notably, mean eGFR slope results with empagliflozin 10 mg and empagliflozin 25 mg were overall consistent with the pooled analyses across all three study periods (Supplemental Figure 2).
Empagliflozin slowed the annual decline in eGFR assessed by mean eGFR slopes based on random-intercept/random-coefficient models. Overall population, pooled empagliflozin groups. (A) Adjusted mean eGFR over prespecified study periods. (B) Change in eGFR per week or year during prespecified study periods. All patients were treated with one or more doses of study drug. Adjusted mean slopes represent the average change in eGFR (Modification of Diet in Renal Disease) per week (for initiation and cessation) and per year (for chronic maintenance treatment) for prespecified study periods. 95% CI, 95% confidence interval; LVOT, last value on treatment.
Mean eGFR Slopes in Subgroups of Patients at Higher Risk for Progressive CKD
In patients with prevalent CKD at baseline, mean slopes depicting weekly/annual changes in eGFR during the treatment initiation period, the chronic maintenance treatment period, and the postdrug cessation period for empagliflozin (pooled) and placebo are shown in Figure 4A. Differences in mean adjusted annual eGFR slope rates during chronic therapy were in favor of empagliflozin compared with placebo, with no significant difference between patients with or without prevalent CKD at baseline (Figure 5), and these results were overall consistent with the effects observed in the overall study population. Detailed mean eGFR slope results for prevalent CKD subgroups across all three prespecified study periods are depicted in Supplemental Figure 3A. In addition, differences in weekly mean eGFR slope rates for empagliflozin versus placebo were consistent in patients with and without prevalent CKD during both the initiation and cessation time periods (Supplemental Figure 4).
Empagliflozin slowed the annual decline in eGFR in patient subgroups at higher risk for CKD progression assessed by mean eGFR slopes based on random-intercept/random-coefficient models. Adjusted mean eGFR across subgroups on the basis of baseline characteristics for (A) prevalent CKD, (B) urinary albumin-to-creatinine ratio (UACR), (C) race, (D) BP, (E) age, and (F) glycated hemoglobin A1c (HbA1c). DBP, diastolic BP; EMPA, empagliflozin; PBO, placebo; SBP, systolic BP; SE, SEM.
Annual changes in eGFR slope favored empagliflozin over placebo in the overall population and in subgroups. Differences in mean eGFR slopes (Modification of Diet in Renal Disease; milliliters per minute per 1.73 m2) between empagliflozin and placebo during chronic treatment (week 4 to last value on treatment) in the treated set of the overall study population and patient subgroups. Measurements obtained during study drug intake were used. Differences depicted for individual data points between empagliflozin and placebo groups represent differences in the annual change in kidney function. Data were from a random-intercept/random-coefficient model. 95% CI, 95% confidence interval; HbA1c, glycated hemoglobin A1c. *Prevalent CKD was defined as eGFR<60 ml/min per 1.73 m2 and/or macroalbuminuria (urinary albumin-to-creatinine ratio [UACR] >300 mg/g). †Normo indicates normoalbuminuria (UACR<30 mg/g), micro indicates microalbuminuria (UACR=30–300 mg/g), macro indicates macroalbuminuria (UACR>300 mg/g).
A similar pattern of adjusted mean eGFR weekly/annual slopes during the initiation, chronic maintenance treatment, and cessation periods for empagliflozin and placebo was seen in further analyses for subgroups on the basis of baseline UACR (Figure 4B), race (Figure 4C), BP (Figure 4D), age (Figure 4E), and baseline HbA1c (Figure 4F). As with the overall patient population, adjusted mean annual eGFR slope rates during chronic therapy were stable with empagliflozin compared with a decline in placebo in most of the subgroups, and they were smaller with empagliflozin compared with placebo in all subgroups (Figure 5). Notably, we identified potential heterogeneity in the treatment effect of empagliflozin during chronic treatment maintenance for two at-risk patient subgroups: the placebo-corrected numerical treatment effect of empagliflozin on slowing annual decline in eGFR seemed to be larger in patients with macroalbuminuria or increased BP levels compared with patients with lower levels of albuminuria or BP at baseline (P values for interaction <0.001 and <0.02, respectively) (Figure 5). Further detailed mean eGFR slopes data for the patient subgroups across all three prespecified study periods are depicted in Supplemental Figure 3, B–F.
Discussion
This study supports the hypothesis that empagliflozin treatment results in consistent shifts in individual patient eGFR slopes during the three prespecified study periods: a leftward shift (i.e., eGFR decline relative to placebo) shortly after initiation (indicative of an acute hemodynamic response), a rightward shift (i.e., slowing of eGFR loss relative to placebo) during chronic maintenance treatment (indicative of preserving kidney function), and a rightward shift (i.e., increase in eGFR relative to placebo) shortly after drug cessation (indicative of a reversal of the renal hemodynamic effect—even after long-term drug intake). This dynamic eGFR slope pattern was also consistent across patients with an array of eGFRs in the trial and specifically across subgroups of patients at higher risk of CKD progression. Interestingly, we found an indication for a more pronounced effect of empagliflozin to slow kidney function decline in patients with prevalent macroalbuminuria or increased BP. Individuals with these clinical conditions are known to be at increased risk for rapid decline in kidney function, and our hypothesis-generating findings merit future clinical research. Further assessment of eGFR slope in patients with type 2 diabetes, albeit during shorter-term treatment and lacking a postdrug follow-up period, has previously been reported for another SGLT2 inhibitor, canagliflozin.16
Historically, doubling of serum creatinine level, which roughly equates to a 57% reduction in eGFR, has been used as an end point in clinical studies of kidney disease.15,17,18 Use of this measure, however, necessitates lengthy follow-up and/or very large numbers of patients in clinical trials, because doubling of serum creatinine is a late manifestation of CKD progression. Consequently, much effort is being devoted to exploring novel alternative measures of kidney disease progression for use as a more effective metric of CKD progression. This initiative also aims to reduce complexity and logistical burden for investigators and patients in clinical research as well as enable the study of individuals with earlier-stage CKD. One such potential alternative end point under discussion is the rate of change in kidney function over time (i.e., eGFR slope).15,19
We propose that eGFR slopes may be considered as a surrogate end point for future clinical research in CKD/diabetic kidney disease under certain conditions where relevant prerequisites are fulfilled. First, a population in need of additional kidney-protective therapy (e.g., individuals with a clinically meaningful decline in annual eGFR slope) has to be defined. Second, a clinically relevant treatment effect of the specific intervention (e.g., a minimal expected slowing in annual GFR decline) should be prespecified. Third, the minimum duration of a chronic maintenance treatment effect should be ensured. For example, in the EMPA-REG OUTCOME Trial, such criteria apply to the subgroups of patients with prevalent CKD: a clinically relevant treatment effect with empagliflozin (compared with a clinically relevant annual decline in kidney function in the placebo group) accompanied by an appropriate duration for which the drug effect was maintained. Additional investigations are needed to clarify clinically relevant effect sizes and the minimal duration of chronic treatment effects for a range of drugs and conditions (including interventions with acute hemodynamic effects). Such investigations will help to standardize eGFR slope analysis in future clinical trials.
Our prespecified slope analysis of the EMPA-REG OUTCOME Trial shows that empagliflozin treatment was associated with a consistent shift in individual eGFR slopes (independent of the underlying rate of GFR change) during the three study periods, in particular showing evidence for homogeneity during the chronic maintenance treatment period (the most clinically relevant period). The latter phenomenon is referred to as a uniform treatment effect.15,20 The alternative, where the effect of an intervention is stronger for faster-progressing patients than for slower-progressing patients, has been termed the proportional treatment effect model.15,20 In this latter scenario, the treatment effect is proportional to the underlying rate of eGFR decline that would have been observed if no intervention was applied. If a proportional effect is present, using mean eGFR slope may be less advantageous compared with a dichotomous outcome (e.g., a time to event analysis), because the treatment effect may be diluted by the inclusion of patients with less progressive disease. We consider that the consistent shifts in individual eGFR slope during the chronic maintenance treatment period observed in the EMPA-REG OUTCOME Trial are in line with the uniform treatment effects model, which supports the use of annual mean eGFR slope as a surrogate end point in future clinical trials with SGLT2 inhibitors.
Our results presented here have strengths and limitations. Analyses were prespecified and are considered of high internal validity, because eGFR slopes were assessed on the basis of recurrent standardized testing. This allowed for annual eGFR slope assessments on the basis of repeated measurements during the chronic maintenance treatment period; however, changes during the initiation and postdrug cessation periods were limited by two consecutive eGFR measurements and therefore, cannot definitively quantify the slope during these two phases. Our results are indicative of treatment effects of empagliflozin during active intake of study drug, because eGFR measurements after premature discontinuation of study drug were censored. This approach envisages determining the biologic effect of the drug; however, this methodology can also lead to potential selection bias of patients during the three prespecified study periods, and extrapolation of findings to the entire trial population has limitations. Moreover, direct comparisons between eGFR changes during the initiation and post-treatment periods should also be interpreted with caution. Nevertheless, the sample size of the overall population enabled the identification of meaningful numbers of patients at higher risk of progressive CKD, providing further confidence in the kidney effects of empagliflozin. Conversely, the EMPA-REG OUTCOME Trial was primarily designed as a cardiovascular trial, and eGFR<30 ml/min per 1.73 m2 at screening was grounds for exclusion. Therefore, a limited number of definitive kidney outcomes were available to validate changes in eGFR slope against traditional kidney outcomes, such as doubling of serum creatinine and RRT. Hence, future studies are needed to explore the effect of empagliflozin and other SGLT2 inhibitors on kidney function decline in individuals at more advanced stages of CKD, including those without diabetes. A large kidney outcomes study of empagliflozin including patients with and without diabetes (the EMPA-KIDNEY Study) will start in 2018. Additional insights into the kidney effects of other SGLT2 inhibitors, including eGFR slope analyses, are expected to emerge from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial,21 the Dapagliflozin Effect on CardiovascuLAR Events Thrombolysis in Myocardial Infarction Trial,22 and the DAPA-CKD Trial (ClinicalTrials.gov: NCT03036150) involving canagliflozin or dapagliflozin.
Our comprehensive slope analysis shows that empagliflozin has the potential to significantly slow eGFR decline over a treatment period of approximately 3 years, including in patients at higher risk for progressive kidney disease. Moreover, empagliflozin slope patterns are indicative of a renal hemodynamic effect reminiscent of observations with ACE inhibitors or ARBs: an initial transient decline in eGFR followed by long-term slowing of kidney function loss.23,24 After cessation of empagliflozin, eGFR slopes showed a swift upward trajectory toward baseline, suggestive of an immediate reversibility of the renal hemodynamic effect. Further studies may facilitate specific statistical models to assess the utility of slopes as an attractive surrogate end point of kidney disease progression in clinical research.
Disclosures
C.W. reports honoraria from Boehringer Ingelheim (the manufacturer of empagliflozin), Eli Lilly, Mitsubishi, and MSD. H.J.L.H. has consultancy agreements with the following companies: AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Janssen, Fresenius, and Merck; H.J.L.H. has a policy of honoraria going to his employer. B.Z. has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis. S.E.I. reports honoraria from Intarcia Therapeutics, Inc.; Daiichi-Sankyo; Lexicon Pharmaceuticals; Janssen; Sanofi; AstraZeneca; Boehringer Ingelheim; and Novo Nordisk. A.K.-W., M.M., S.H., U.C.B., and M.v.E. are employees of Boehringer Ingelheim. H.-J.W. was an employee of Boehringer Ingelheim at the time of the study.
Acknowledgments
Editorial assistance with compilation of the methods and results sections and preparing figures, supported financially by Boehringer Ingelheim, was provided by Giles Brooke and Geraldine Thompson of Envision Scientific Solutions during the preparation of this manuscript.
Data from this study were previously presented at the American Society of Nephrology Kidney Week November 15–20, 2016 in Chicago, Illinois and the American Diabetes Association 77th Scientific Sessions June 9–13, 2017 in San Diego, California.
The EMPA-REG OUTCOME Investigators are as follows:
Argentina: D. Aizenberg, Centro Médico Viamonte, Capital Federal, BS AS; M. Ulla, ILAIMCEOM, Córdoba, CBA; J. Waitman, Centro Diabetologico Dr Waitman, Córdoba, CBA; L. De Loredo, Hospital Privado - Centro Médico de Córdoba S.A., Parque Velez Sarfield, CBA; J. Farías, H. Fideleff, Sanatorio Güemes, Capital Federal, BS AS; M. Lagrutta, Instituto de Investigaciones Clinicas, Rosario, STA FE; N. Maldonado, Centro Medico de Alta Complejidad, Rosario, STA FE; H. Colombo, Clinica Privada Colombo, Cordoba, CO; F. Ferre Pacora, Centro Médico Colon, Cordoba, CO; A. Wasserman, Fepreva, Buenos Aires, BA; L. Maffei, Consultorios Asociados de Endocrinología e Invest Clínica, Capital Federal, BS AS; Australia: R. Lehman, Adelaide Medical Research, Ashford, SA; J. Selvanayagam, Heart and Vascular Institute, Fullarton, SA; M. d’Emden, Royal Brisbane and Womens Hospital; Herston, QLD; Austria: P. Fasching, Wilhelminenspital Wien, Wien; B. Paulweber, LKH Salzburg - St. Johanns-Spital, Salzburg; H. Toplak, Medical University Graz, Graz; A. Luger, Univ.-Klinik für Innere Medizin III, Wien; H. Drexel, Landeskrankenhaus Feldkirch, Feldkirch; R. Prager, Krankenhaus Hietzing mit NZR, Wien; C. Schnack, G. Schernthaner, Krankenanstalt Rudolfstiftung inkl. Semmelweis Frauenklinik, Wien; G. Schernthaner, Univ. Klinik für Innere Medizin II, Wien; E. Fliesser-Görzer, Ordination Dr. Fliesser-Görzer, St. Stefan; S. Kaser, Universitätsklinik Innsbruck, Innsbruck; Belgium: A. Scheen, Centre Hospitalier Universitaire de Liège, Liège; L. Van Gaal, UZA, Edegem; G. Hollanders, Dr. Geert Hollanders, De Pinte; Y. Kockaerts, Ziekenhuis Oost Limburg, Genk; L. Capiau, Dr. Luc Capiau, Massemen-Wetteren; A. Chachati, CHR Huy, Huy; A. Persu, M. Hermans, Cliniques Universitaires Saint-Luc, Bruxelles; D. Vantroyen, Huisartsenpraktijk Hygeia, Hasselt; C. Vercammen, Imelda ZH Bonheiden, Bonheiden; P.Van de Borne, Hôpital universitaire Erasme, Bruxelles; K. Benhalima, C. Mathieu, UZ Gasthuisberg, Leuven; F. Lienart, CHU de Tivoli, La Louvière; J. Mortelmans, Private Practice, Oostham; M. Strivay, CHR de la Citadelle - Site Citadelle, Liège; G. Vereecken, Dr Guy Vereecken, Halen; B. Keymeulen, F. Lamkanfi, UZ Brussel, Brussel; Brazil: A. Chacra, Hospital São Paulo UNIFESP, Villa Clementino, SP; F. Eliaschewitz, Centro de Pesquisas Clínicas Ltda, Higienópolis, SP; M. Zanella, Hospital do Rim e Hipertensão, Vila Clementino, SP; A. Faludi, M. Bertolami, Instituto Dante Pazzanese De Cardiologia, São Paulo, Brasil; C. Hayashida, Blumenau Serviços Médicos S/C Ltda, Vila Leopoldina, SP; J. Nunes Salles, O. Monte, Salles, Irmandade da Santa Casa de Misericórdia de São Paulo, Vila Albuquerque, SP; M. Dinato, Centro de Pesquisas Clinicas do Hospital Guilherme Álvaro, Boqueirão, ST; E. Manenti, Hospital Mãe de Deus, Porto Alegre, RS; N. Rassi, Hospital Geral de Goiânia, Goiânia, Brasil; A. Halpern, Hospital das Clinicas de Sao Paulo – FMUSP, São Paulo, Brasil; M. Lima Filho, Hospital Electro Bonini Universidade de Ribeirão Preto, Ribeirão Preto, BR; J. Ayoub, Instituto de Molestias Cardiovasculares – IMC, São José do Rio Preto, BR; J. Felicio, Hospital Universitário João de Barros Barreto, Belém, PA; J. Borges, Centro de Pesquisa Clínica do Brasil, Brasília, BR; J. Gross, Centro de Pesquisas em Diabetes, Porto Alegre, RS; J. Sgarbi, Hospital de Clinicas da Faculdade de Medicina de Marilia, Marilia, BR; R. Betti, Instituto do Coração, São Paulo, Brasil; A. Tiburcio, S. Purisch, Santa Casa de Misericordia de Belo Horizonte, Belo Horizonte, BR; H. Schmid, Irmandade Santa Casa de Misericordia de Porto Alegre, Porto Algre, BR; M. Takahashi, Universidade Estadual de Maringá, Maringá, BR; M. Castro, Instituto de Pesquisa Clínica e Medicina Avançada, São Paulo, BR; R. Rea, Universidade Federal do Paraná, Curitiba, BR; M. Hissa, Centro de Pesquisas em Diabetes e Doenças, Fortaleza, Brasil; B. Geloneze Neto, Ced Centro de Endocrinologia e Diabetes, Campinas, Brasil; J. Saraiva, Hospital e Maternidade Celso Peirro – PUCCAMP, Campinas, Brasil; Canada: S. Henein, SKDS Research Incorporated, Newmarket, ON; H. Lochnan, Ottawa, ON; S.A. Imran, D. Clayton, QEII Health Sciences Centre, Centre for Clinical Research, Halifax, NS; K. Bayly, Mount Royal Family Physicians, Saskatoon, SK; J. Berlingieri, Burlington, ON; P. Boucher, Longueuil, QC; Y. Chan, Niagara Falls, ON; M. Gupta, Brampton, ON; R. Chehayeb, A. Ouellett, ViaCar Recherche Clinique Inc, Longueuil, QC; E. Ur, Vancouver, BC; V. Woo, Winnipeg, MB; B. Zinman, Toronto, ON; E. St. Amour, Q&T Research Outaouais, Gatineau, QC; Colombia: M. Terront Lozano, UNIENDO Unidad Integral de Endocrinologia, Bogotá, Colombia; H. Yupanqui Lozno, Dexa-Diab IPS, Bogotá, CO; M. Urina, Fundación del Caribe para la Investigación Biomédica, Barranquilla, Atlantico; P. Lopez Jaramillo, Fundación Oftalmologica de Santander, Floridablanca, CO; N. Jaramillo, CEMDE, Medellín, CO; G. Sanchez, CEQUIN, Armenia, CO; G. Pérez, Cardiolab Ltda., Bogotá, CO; Croatia: S. Tusek, Specialized Hospital for Medical Rehabilitation, Krapinske Toplice; G. Mirosevic, V. Goldoni, University Hospital Centre 'Sestre Milosrdnice', Zagreb; D. Jurisic-Erzen, University Hospital Centre Rijeka, Rijeka; A. Balasko, S. Balic, General Hospital Sveti Duh, Zagreb; E. Drvodelic-Sunic, General Hospital Karlovac, Karlovac; S. Canecki Varzic, Clinical Hospital Centre Osijek,Osijek; Czech Republic: M. Machkova, CCBR Czech Prague s.r.o., Praha 3; P. Weiner, Diabetology Out Patient Clinic of Hospital Jindrichuv Hradec, Jindrichuv Hradec; J. Lastuvka, Masaryk Hospital, Usti nad Labem; J. Olsovsky, St. Anna Hospital, Brno; Denmark: T. Krarup, Bispebjerg Hospital, København NV; M. Ridderstråle, L. Tarnow, T. Welløv Boesgaard, Steno Diabetes Center, Gentofte; A. Sætre Lihn, Regionshospitalet Randers, Randers NØ; P. Christensen, H. Juhl, Slagelse Sygehus, Slagelse; S. Urhammer, Frederiksberg Hospital, Frederiksberg; P. Lund, Forskningscentret Nordsjællands Hospital, Helsingør; Estonia: B. Adojaan, Tartu Endocrinology Centre, Tartu; Ü. Jakovlev, East Tallinn Central Hospital, Tallin; R. Lanno, Merelahe Family Doctors Centre, Tallinn; M. Lubi, T. Marandi, Tartu University Hospital, Tartu; T. Marandi, North Estonia Medical Centre Foundation, Tallin; France: D. Gouet, HOP Saint Louis, La Rochelle Cedex 1; J. Courrèges, CH Narbonne, Narbonne Cedex; P. Zaoui, Chu de Grenoble, Grenoble; G. Choukroun, Chu Sud, Amiens; C. Petit, Centre Hospitalier Général Sud Francilien, Corbeil Essonnes; L. Formagne, Cabinet Médical, Derval; B. Estour, Hôpital Nord, Saint Priez en Jarez; P. Mabire, Cabinet Médical, Fleury sur Orne; C. Daugenet, Cabinet Médical, Equeurdreville Haineville; B. Lemarie, Cabinet Médical, Bourg descptes; S. Clavel, Hôpital Hôtel Dieu, Le Creusot; P. Aure, Cabinet Médical, Angers; P. Remaud, Cabinet Médical, Angers; J. Halimi, CHU de Tours, Tours; S. Hadjadj, Hôpital de Poitiers, Poitiers; T. Couffinhal, Hôpital Cardiologique du Haut Levèque, Pessac; Georgia: S. Glonti, Unimed Ajara LLC, Batumi; D. Metreveli, David Metreveli Medical Centre Ltd., Tbilisi; Z. Lominadze, L&J Clinic, Kutaisi; E. Giorgadze, National Institute of Endocrinology Ltd., Tbilisi; T. Burtchuladze, L. Javashvili, Chemotherapy & Immunotherapy Clinic “Medulla”, Tbilisi; G. Kurashvili, R. Kurashvili, National Center for Diabetes Research Ltd., Tbilisi; D. Virsaladze, Medical Centre Medelite Ltd., Tbilisi; L. Nadareishvili, A. Khomasuridze, Zhordania Institute of Human Reproduction, Tbilisi; United Kingdom: T. Cahill, The Research Unit, Frome, Somerset; F. Green, NHS Dumfries & Galloway, Dumfries; S. MacRury, Highland Diabetes Institute, Inverness; M. Waldron, A. Middleton, Fowey River Practice, Fowey; J. McKnight, Western General Hospital, Edinburgh; E. Pearson, NHS Tayside, Dundee; M. Butler, Waterloo Medical Centre, Blackpool; M. Choksi, I. Caldwell, Swan Lane Medical Centre, Bolton; I. Farmer, Stanwell Road Surgery, Ashford; N. Wyatt, J. Patrick, The Health Centre, Bradford on Avon; I. O'Brien, NHS Lanarkshire, Wishaw; M. Devers, NHS Lanarkshire, Airdrie, Lanarks; Greece: S. Bousboulas, S. Pappas, General Hospital of Nikaia, Nikaia; G. Piaditis, General Hospital of Athens “G. Gennimatas”, Athens; A. Vryonidou, “Korgialenio-Benakio”, Hellenic Red Cross Hospital, Athens; N. Tentolouris, General Hospital of Athens “Laiko”, Athens; K. Karamitsos, General Hospital of Larissa, Larissa; C. Manes, General Hospital “Papageorgiou”, Thessaloniki; M. Benroubi, General Hospital of Athens “Polikliniki”, Athens; I. Avramidis, General Hospital of Thessaloniki “G. Papanikolaou”, Thessaloniki; Hong Kong: R. Ozaki, Prince of Wales Hospital, Hong Kong; K. Tan, Queen Mary Hospital, Hong Kong; S. Siu, T. Ip, Tung Wah Eastern Hospital, Hong Kong; C. Tsang, Alice Ho Miu Ling Nethersole Hospital, Hong Kong; Hungary: M. Dudas, Bekes County Pandy Kalman Hospital, Gyula; K. Nagy, Synexus Hungary Ltd., Budapest; C. Salamon, Clinfan SMO Ltd., Szekszard; L. Gerö, Semmelweis University, Budapest; J. Patkay, Szent Pantaleon Hospital, Dunaujvaros; A. Tabak, G. Tamas, Semmelweis University, Budapest; F. Juhasz, CEE Research Kft., Kisvarda; I. Szentpeteri, CRU Hungary Kft., Szikszo; India: N. Ghaisas, Shatabbdi Superspeciality Hopsital, Nashik, Maharashtra; G. Bantwal, St. Johns Medical College and Hospital, Bangalore; V. Mohan, Dr Mohan's Diabetes Specialities, Chennai; J. Gupta, S. R. Kalla Gastroentoroly & General Hospital, Jaipur; N. Sadhu, Shree Krishna Hospital and Heart Care Centre, Ahmedabad, Ahmedabad; A. Kulkarni, Deendayal Memorial Hospital, Pune, Pune; N. Garg, Tagore Hospital and Heart Care Centre, Jalandhar; S. Reddy, Sumana Hospital, Hyderabad; N. Deshpande, Spandan Heart Institute and Research Centre, Nagpur; K. Gutlapalli, Dr. Ramesh Cardiac and Multispecialty Hospital Ltd, Vijaywada; M. Pillai, Lakshmi Hospital, Cochin; R. Premchand, Krishna Institute of Medical Sciences, Secunderabad; M. Badgandi, Manipal Hospital, Bangalore, Karnataka; S. Jain, TOTAL Diabetes Hormone Institute, Indore, Madhya Pra; S. Aravind, DIACON Hospital & Research Center, Bangalore, NA; P. Shamanna, Bangalore Clinisearch, Bangalore; A. Pandey, Heritage Hospital Ltd., Varanasi, UP; S. Gupta, Diabetes Care n Research Centre, Nagpur; Indonesia: B. Pramono, Sardjito Hospital, Yogyakarta; H. Dante Saksono, Cipto Mangunkusumo Hospital, Jakarta; P. Agung, Soetomo Hospital, Surabaya; S. Djoko Wahono, Saiful Anwar Hospital, Malang; K. Suastika, Sanglah Hospital, Denpasar, Bali; Y. Tanggo, Rumah Sakit FK UKI, Jakarta; Y. Juwana, Cinere Hospital, Depok; B. Siswanto, Harapan Kita National Cardiovascular Center, Jakarta; Israel: F. Adawi, ZIV Medical Center, Safed; S. Efrati, Assaf Harofeh Medical Center, Zerifin; E. Mazen, Haemek Medical Centre, Afula; A. Bashkin, T. Herskovits, Western Galilee Hospital, Nahariya; A. Jaffe, Hillel Yaffe Medical Center, Hadera; E. Schiff, Bnai Zion Medical Center, Haifa; J. Wainstein, The E. Wolfson Medical Center, Holon; Italy: S. Taddei, Dipartimento Medicina Interna, Pisa, IT; A. Aiello, U.O.C. Endocrinologia, Diabetologia e Malattie Metaboliche, Campobasso, IT; M. Arca, Dipartimento di Clinica e Terapia Medica, Roma, IT; P. Calabro, U.O.C. di Cardiologia, Napoli, IT; M. Cignarelli, Dipartimento di Scienze Mediche, Foggia, IT; P. Fioretto, Azienda Ospedaliera di Padova, Padova, IT; G. Marchesini Reggiani, Policlinico “S. Orsola-Malpighi”, Bologna, IT; A. Gnasso, A:o. “Mater Domini”, Catanzaro, IT; N. Marchionni, A. Marsilii, A.O. “Careggi”, Firenze, IT; M. Bucci, A. Mezzetti, Fondazione Università “G. D'Annunzio”, Chieti, IT; P. Pozzilli, Area Endocrinologia, Roma, IT; F. Colivicchi, M. Santini, Divisione di Cardiologia, Roma, IT; E. Moro, A. Semplicini, U.O. di Mediicna Interna, Venezia, IT; V. Toscano, U.O.C. Endocrinologia, Roma, IT; A. Fucili, Centro per lo Scompenso Cardiaco, Ferrara, I; Japan: S. Monno, Chibanishi General Hospital, Matsudoshi, Chiba; K. Furui, Hanyu General Hospital, Hanyushi, Saitama; S. Higashiue, N. Hiramatsu, Kishiwada Tokushukai Hospital, Kishiwadashi. Osaka; K. Kawamitsu, Okinawa Tokushukai medical corporation, Shimajiri-gun,Okinawa; T. Takenaka, National Hospital Organization Hokkaido Medical Center, Nishi-ku, Sapporoshi, Hokkaido; H. Takahashi, Iryouhouijneiwakai Minamiakatsuka clinic, Mitoshi, Ibaraki; F. Hojo, Kobari General Hospital, Nodashi, Chiba; Y. Onishi, The Institute for Adult Diseases, Chuo-ku, Tokyo; K. Izumino, Fujikoshi Hospital, Toyamashi, Toyama; M. Okubo, Gifu Heart Center, Gifushi, Gifu; Y. Wakida, Daishinkai Medical Corporation Ookuma Hospital, Kita-ku, Nagoyashi, Aichi; Y. Kondo, Clinic Horikawa, Kamigyo-ku, Kyotoshi, Kyoto; K. Hieshima, H. Jinnouchi, Jinnouchi Diabetes Center, Kumamoto-shi, Kumamoto; A. Suzuki, M. Ito, Fujita Health University Hospital, Toyoakeshi, Aichi; Republic of Korea: S. Park, Severance Hospital, Seoul, NA; Y. Kim, Asan Medical Center, Seoul; T. Hong, Pusan National University Hospital, Pusan; H. Park, Kyungpook National University Hospital, Daegu; H. Gwon, Samsung Medical Center, Seoul; H. Kim, Seoul National University Hospital, Seoul; K. Kang, S. Lee, Eulji University Hospital, Daejeon; M. Jeong, Chonnam National University Hospital, Gwangju; K. Seung, The Catholic University of Korea, Seoul; D. Lim, Korea University Anam Hospital, Seoul; S. Rha, Korea University Guro Hospital, Seoul; S. Tahk, Ajou University Hospital, Suwon; J. Yang, National Health Insurance Service Ilsan Hospital, Goyang; J. Yoon, Wonju Severance Christian Hospital, Wonju; M. Shin, Gachon University Gil Medical center, Incheon; D. Kim, Inje University Haeundae Paik Hospital, Busan; J. Jeong, Chungnam National University Hospital, Daejoen; Malaysia: N. Nik Ahmad, Hospital Tengku Ampuan Afzan, Pahang; N. Mustafa, Pusat Perubatan University, Kuala Lumpur; W. Wan Mohamed, Hospital Universiti Sains Malaysia, Kelantan; Y. Fung, Queen Elizabeth Hospital, Kota Kinabalu; R. Abdul Ghani, A. Chandramouli, Universiti Teknologi Mara, Selangor; K. Chee, University Malaya Medical Centre, Kuala Lumpur; K. Abdul Kadir, Monash University (Sunway Campus), Selangor Darul Ehsan; K. Ling, Hospital Sultanah Aminah, Johor Bahru; M. Abu Hassan, Hospital Sultanah Bahiyah, Kedah; S. Foo, Hospital Selayang, Selangor; Mexico: P. Garcia Hernandez, Hospital Universitario de Nuevo Leon, Monterrey, Nl; C. Aguilar-Salinas, Instituto Nacional de Ciencias Médicas y Nutrición, Distrito Federal, Mex; M. Vidrio Velazquez, Unidad de Investigacion Clinica Cardiometabolica, Colonia Americana, Gua; F. Flores, Hospital Dr. Angel Leaño, Los Robles, Mex; M. Alpizar Salazar, Centro Especializado de Diabetes, Reforma Social, Mex; D. Micher Escalante, M. Garcia Soria, Clinical Research Institute, San Lucas tepetlcalco, Mex; E. Cardona Muñoz, ICLE SC, Ladron de Guevara, MEx; Netherlands: G. Storms, St. Antonius Ziekenhuis, Utrecht; N. Schaper, Maastricht UMC+ (UM en azM werken samen onder de naam Maastricht UMC+), Maastricht; A. Kooy, Bethesda Ziekenhuis, Hoogeveen; M. Krekels, Orbis Medisch Centrum, Geleen; T. Bemmel van, R. Verhoeven, Gelre Ziekenhuizen Apeldoorn, Apeldoorn; H. Mulder, Rotterdam Research Institute, Rotterdam; P. Oldenburg-Ligtenberg, Meander Medisch Centrum, locatie Amersfoort Lichtenberg, Amersfoort; F. Gonkel, Ropcke-Zweers Ziekenhuis, Hardenberg; A. Jong de, Huisartsenpraktijk De Hooge Boom, Hoogwoud; J. Soest van, Huisartsenmaatschap LSV, Nijverdal; P. Viergever, Gemini Ziekenhuis, Den Helder; H. Mevissen, Huisartsenpraktijk Wildervank, Wildervank; G. Lochorn, Medisch Centrum Gorecht, Hoogezand; G. Zwiers, Vlietland Ziekenhuis, Schiedam; P. Hoogslag, Diaconessenhuis Meppel, Meppel; E. Ronner, Reinier de Graaf Gasthuis, Delft; P. Nierop, Sint Franciscus Gasthuis, Rotterdam; N. Al – Windy, Gelre Ziekenhuizen locatie Zutphen, Zutphen; J. Kragten, Atrium Medisch Centrum, locatie Heerlen, Heerlen; P. Dekelver, Huisartsenpraktijk Dekelver, Baarle - Nassau; New Zealand: J. Benatar, Auckland City Hospital, Grafton / Auckland; J. Krebs, Wellington Hospital, Wellington; R. Scott, Christchurch Hospital Campus, Christchurch; Norway: E. Heggen, Oslo Universitetssykehus HF, Oslo; A. Berz, Medisinsk Senter Fornebu, Fornebu; C. Fossum, Sykehuset Innlandet HF, Gjøvik; U. Hurtig, Sykehuset Innlandet HF, Avd. Tynset, Tynset; G. Langslet, Oslo Universitetssykehus HF, Oslo; M. Baranowski, Intern Medic, Trondheim; J. Sparby, Sykehuset Innlandet HF, Kongsvinger, Kongvinger; T. Karlsson, Dr. Thomas Karlsson, Kløfta; Peru: C. Delgado Torres, Instituto Delgado de Investigacion Medica, Arequipa, PE; A. Rodriguez Escudero, Hospital Alberto Sabogal Sologuren, Bellavista, PE; R. Lisson, Hospital Nacional Edgardo Rebagliati Martins, Jesus Maria, Lima; A. Allemant Maldonado, Hospital Nacional Hipólito Unanue, El Agustino, PE; W. Gallardo Rojas, Instituto Medico Miraflores, Miraflores, PE; L. Gonzales Bravo, Clinica Medica San Martin, Ica, PE; J. Lema Osores, Hospital Nacional Arzobispo Loayza, Lima, PE; J. Farfan, Instituto Endocrinologico Farfan, Arequipa, PE; L. Zapata, Casa de Diabetes & Nutrición, Lima, PE; J. Godoy Junchaya, Hospital Nacional Daniel Alcides Carrión, Lima, PE; Y. Roldan Concha, J. Urquiaga Calderon, Centro de Investigación Heart Help, Lima, LI; Philippines: R. Sy, Cardinal Santos Medical Center, Manila; G. Tan, Cebu Doctors University Hospital, Cebu; G. Aquitania, Philippine Nikkei Jin Kai Polyclinic and Diagnostic Center, Davao; G. De Los Santos, Metropolitan Medical Center, Manila; A. Panelo, UERM-Institute for Studies on Diabetes Foundation,Inc, Marikina City; O. Roderos, De La Salle University Medical Center, Cavite City; R. Rosales, Metropolitan Medical Center, Manila; R. Toledo, Señor Santo Niño Hospital, Tarlac; A. Liwag, West Visayas State University Medical Center, Jaro Iloilo City; H. Ramoncito, Amang Rodriguez Medical Centre, Marikina City; Poland: E. Skokowska, NZOZ Przychodnia Specjalistyczna “Medica”, Lublin; E. Krzyzagorska, Private Practice Dr. Ewa Krzyzagorska, Poznan; M. Ogorek, NZOZ All-Med Medical Centre, Lodz; L Wojnowski, Citomed Sp. Z.o.o., Torun; J. Spyra, Specialized Practice Dr. Janusz Spyra, Ruda Slaska; M. Konieczny, Specialized Physician's Office Ko-Med, Pulawy; W. Piesiewicz, Medical Centre Hospital Swietej Rodziny, Lodz; W. Kus, Individual Specialized Practice, Lodz; A. Ocicka-Kozakiewicz, Non-Public HealthCare Center “Nasz Lekarz”, Torun; E. Orlowska-Kunikowska, University Clinical Center, Gdansk; W. Zmuda, Oswiecimskie Centrum Badan Klinicznych Medicome Sp. z o.o., Oswiecim; Portugal: S. Duarte, Centro Hospitalar Lisboa Ocidental, Lisboa; A. Leitão, Centro Hospitalar Lisboa Central, Lisboa; P. Monteiro, Hospitais da Universidade de Coimbra, Coimbra; H. Rita, Unidade de Saúde do Litoral Alentejano, EPE, Santiago do Cacém; V. Salgado, Hospital Fernando Fonseca, Amadora; L. Pinto, Centro Hospitalar de Leiria-Pombal, EPE, Leiria; J. Queirós, Hospital de São João, Porto; J. Teixeira, Unidade Local de Saúde do Alto Minho, Viana do Castelo; C. Rogado, R. Duarte, APDP-Associação Protectora dos Diabéticos de Portugal, Lisboa; F. Sobral do Rosário, Hospital da Luz, Lisboa; A. Silva, Centro Hospitalar do Algarve, EPE, Faro; L. Andrade, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia; M. Velez, Centro Hospitalar Médio Tejo, EPE, Torres Novas; M. Brazão, Serviço Região Autónoma da Madeira, EPE, Funchal, Madeira; Romania: O. Istratoaie, SC Cardiocenter Dr. Istratoaie SRL, Craiova; R. Lichiardopol, Institute of Diabetes Nutrition and Metabolic Diseases, Bucharest; D. Catrinoiu, County Clinical Hospital, Constanta; C. Militaru, S.C. Cardiomed S.R.L, Craiova; C. Zetu, Institute of Diabetes Nutrition and Metabolic Diseases, Bucharest; D. Barbonta, SC Diana Barbonta SRL, Alba Iulia; D. Cosma, Pelican Impex SRL, Cabinet Nr. 15, Oradea; C. Crisan, RAI Medicals SRL, Mediab SRL, Targu-Mures; L. Pop, Cabinet Med. Individual Diabet, Nutritie, Boli Metabolice Private Practice Dr. Lavinia Pop, Baia Mare Maramures; Russia: V. Esip, Saint Petersburg State Healthcare Institution, St. Petersburg, F. Khetagurova, A. Petrov, Vsevolozhsk Central Regional Hospital, Vsevolozhsk; G. Arutyunov, City Clinical Hospital No. 4, Moscow; M. Boyarkin, City Alexander Hospital St. Petersburg, St. Petersburg; A. Agafyina, Saint-Petersburg GUZ “City Clinical Hospital #40, Saint Petersburg; N. Vorokhobina, St. Petersburg GUZ City Clinical Hospital of Saint Elizabeth, St. Petersburg; N. Petunina, City Clinical Hospital No. 67, Moscow; I. Libov, Moscow GUZ City Clinical Hospital named after S.P. Botkin, Moscow; A. Zalevskaya, Autonomous nonprofit organization, St. Petersburg; K. Nikolaev, City Clinical Hospital No. 19, Novosibirsk; O. Barbarash, Heart & Vessels Diseases complex problems, Kemerovo; V. Potemkin, Moscow GUZ City Clinical Hospital No. 68, Moscow; A. Bystrova, E. Krasilnikova, St. Petersburg State Medical Univ. n.a. I Pavlov Roszdrava, St. Petersburg; V. Barbarich, City Clinical Hospital No. 1, Novosibirsk; G. Chumakova, Altai State Medical University, Barnaul; N. Tarasov, Medicosanitary Unit of Main Dept. of Internal Affairs, Kemerovo; T. Meleshkevich, Central Clinical Hospital No. 2, Moscow; D. Zateyshchikov, City Hospital No. 17, Moscow; O. Lantseva, St-Petersburg State Healthcare Institution, St. Petersburg; D. Belenkiy, MUZ Novosibirsk Municipal Clinical Hospital of Emergency No. 2, Novosibirsk; A. Obrezan, LLC International Medical Center SOGAZ, Saint Petersburg; L. Rossolko, City Polyclinic No. 120, Saint Petersburg; E. Fillipova, LLC Medinet, Saint Petersburg; P. Yakhontova, Novosibirsk Regional Clinical, Novosibirsk; A. Khokhlov, MUZ Clinical Hospital #2, Yaroslavl; Singapore: R. Tan, National Heart Center, Singapore; C. Sum, Khoo Teck Puat Hospital, Singapore; H. Chang, Singapore General Hospital, Singapore; South Africa: L. Distiller, Centre For Diabetes and Endocrinology, Houghton; M. Pretorius, Tiervlei Trial Centre, Bellville; H. Nortje, Dr H. Nortje, Goodwood; E. Mitha, Newtown Clinical Research Centre, Newtown; L. Burgess, Tread Research, Parow; S. Blignaut, Paarl Research Centre, Paarl; T. Venter, Cardiology Clinical Research, Alberton; R. Moodley, Dr. Moodley and Dr. Sarvan, Tongaat; J. Lombaard, Josha Research Centre, Bloemfontein; U. Govind, Dr U. Govind, Sydenham; V. Naidoo, Durban, KZN; M. Mookadam, Langeberg Clinical Trials, Cape town, WC; J. Engelbrecht, Vergelegen Medi-Clinic, Somerset West; M. Omar, Centre for Diabetes and Endocrinology, Durban; J. Jurgens, DJW Navorsing, Krugersdorp; G. Podgorski, Greenacres Hospital, Port Elizabeth; H. Vawda, D. Naidoo, Cardiology Research Clinic, Durban, KZN; S. Emanuel, Synopsis Research, Cape Town, WC; A. Roodt, Clinresco Centre (Pty) Ltd, Kempton Park, GAU; A. Amod, Medical Centre, Chatsworth Unit 10, KZN; L. Van zyl, Clinical Projects Research, Worcester, WC; Spain: J. Segura, Hospital 12 de Octubre, Madrid; M. Brito, Hospital Universitario Puerta de Hierro, Mahadahonda (Madrid); A. Fernandez-Cruz, Hospital Clínico Universitario San Carlos, Madrid; S. Artola, Centro de Salud Maria Jesus Hereza, Leganes (Madrid); R. Iglesias, Centro de Salud Pedro Lain Entralgo, Alcorcon (Madrid); E. Toural, Centro de Salud Lavapies, Madrid; L. Garcia-Ortiz, Centro de Salud La Alamedilla, Salamanca; J. Saban, Hospital Universitario Ramon y Cajal, Madrid; J. Mesa, Hospital Vall d’Hebron, Barcelona; J. Vidal, Hospital Clinic i Provincial de Barcelona, Barcelona; J. Linares, Clinica Inmaculada Concepcion, Granada; F. del Cañizo, Hospital Infanta Leonor, Madrid; M. Rigla, Corporacio Sanitaria Parc Tauli, Sabadell (Barcelona); C. Suarez, Hospital Universitario La Princesa, Madrid; I. Llorente, Hospital Nuestra Señora de la Candelaria, Santa Cruz de Tenerife; B. Moreno, Hospital General universitario, Madrid; A. Antoli, F. Gomez Peralta, Hospital Nuestra Señora de Sonsoles, Avila; M. Iglesias, CAP Badía del Vallès, Badía del Vallès – Barcelona; F. Gomez-Peralta, Hospital General de Segovia, Segovia; V Pereg, Hospital Son Espases, Palma de Mallorca; L. de Teresa, Instituto de Ciencias Médicas, Alicante; M. Camafort, Hospital Clinic i Provincial de Barcelona, Barcelona; C. Trescoli, Hospital de la Ribera, Alzira, Valencia; Sri Lanka: R. Satarasinghe, Sri Jayewardenepura General Hospital & PGMI, Nugegoda; N. Somasundaram, National Hospital, Colombo; S. Siyambalapitiya, Colombo North Teaching Hospital, Ragama; C. Antonypillai, Diabetes and Endocrine Unit, Kandy; D. Bulugahapitiya, Diabetes Clinic, Kalubowila; U. Medagama, Teaching Hospital Peradeniya, Kandy; Taiwan: C. Huang, Chung Shan Medical University Hospital, Taichung; Y. Lu, E-Da Hospital, Kaohsiung; J. Hwang, National Taiwan University Hospital, Taipei; C. Chiang, Taipei Veterans General Hospital, Taipei; M. Wen, Chang Gung Memorial Hospital,Linkou, Taoyuan; J. Chen, National Cheng Kung University Hospital, Tainan; W. Lai, Kaohsiung Medical University Hospital, Kaohsiung; K. Chang, China Medical University Hospital, Taichung; J. Wang, Buddhist Tzu Chi General Hospital, Hualien; H. Yeh, Mackay Memorial Hospital, Tamsui, Taipei County; Thailand: P. Kriangsak, Udonthani Hospital, Muang District; C. Deerochanawong, Rajavithi Hospital, Bangkok; S. Suwanwalaikorn, King Chulalongkorn Memorial Hospital, Bangkok; A. Mangklabruks, Maharaj Nakorn Chiangmai Hospital, Chiang Mai; P. Kaewsuwanna, Maharat Nakhon Ratchasima Hospital, Nakhonratchasima; D. Piyayotai, Thammasat University Hospital, Pathum Tani; Ukraine: M. Iabluchanskyi, Clinical Hospital No. 5, Kharkov; O. Samoylov, Scientific Center of Radiation, Kiev; O. Godlevska, City Clinical Hospital of Emergency Care, Kharkov; O. Kovalyova, Kharkiv City Hospital No. 3, Kharkiv; O. Voloshyna, Odessa State Medical University, Odessa; V. Tseluyko, City Clinical Hospital No. 8, Kharkiv; S. Zotov, I. Vykhovanyuk, Clinic for Cardiology “Sertse i sudyny” LTD, Kiev; United States of America: A. Dulgeroff, High Desert Medical Group, Lancaster, CA; R. Mayfield, Mountain View Clinical Research, Greer, SC; M. Zaniewski-Singh, Michelle Zaniewski, M.D., PA, Houston, TX; J. Ullal, J. Aloi, The Strelitz Diabetes Center, Norfolk, VA; R. De La Rosa, Four Rivers Clinical Research, Paducah, KY; J. Mosely, B. Wittmer, Commonwealth Biomedical Research LLC, Madisonville, KY; S. Aronoff, Research Institute of Dallas, Dallas, TX; J. Rosenfeld, M. Seidner, Green and Seidner Family Practice, Lansdale, PA; M. Warren, Physicians East, PA, Greenville, NC; N. Fishman, Diabetes and Endocrine Specialists Inc, Chesterfield, MO; R. Weiss, Maine Research Associates, Auburn, ME; A. Arif, Apex Medical Research, Flint, MI; M. Sandberg, Westcott Medical Center, Flemington, NJ; D. Lewis, Arkansas Primary Care Clinics, Little Rock, AK; E. Ball, Walla Walla Clinic, Walla Walla, WA; R. Graf, MultiCare Specialties Research, Tacoma, WA; C. Breton, International Research Associates, LLC, Miami, FL; R. Tamayo, Genesis Research International, Longwood, FL; R. Richards, W. Cefalu, G. Uwaifo, Louisiana State University, New Orleans, LA; D. Zayour, J. Hoffman, Via Christi Clinic, PA, Wichita, KS; D. Fitz-Patrick, East-West Medical Research, Honolulu, HI; B. Khan, Atlanta Clinical Research Center, Atlanta, GA; K. Blaze, South Broward Research, Pembroke Pines, FL; P. Bressler, North Texas Endocrine Center, Dallas, TX; S. Halpern, D. Chappell, Radiant Research, Inc, Santa Rosa, CA; R. Bergenstal, R. Cuddihy, G. Matfin, International Diabetes Center, Minneapolis, MN; Z. Freedman, Endocrine-Diabetes Care and Resource Center, Rochester, NY; J. Gonzalez-Campoy, Minnesota Center for Obesity, Metabolism, & Edocrinology, PA, Eagan, MN; S. Lerman, The Center for Diabetes and Endocrine Care, Ft. Lauderdale, FL; M. Rendell, Creighton University School of Medicine Diabetes Center, Omaha, NE; S. Sitar, Orange County Research Institute, Anaheim, CA; M. Reeves, Michael L. Reeves, MD, Chattanooga, TN; T. Howard, Medical Affiliated Research Center, Inc, Huntsville, AL; J. Soufer, Chase Medical Research, LLC, Waterbury, CT; B. Miranda-Palma, University of Miami/ Diabetes Research Institute, Miami, FL; A. Laliotis, Integrated Research Center, San Diego, CA; M. Shomali, Union Memorial Hospital Diabetes and Endocrine Center, Baltimore, MD; M. Teltser, A & R Research Group, LLC, Pembroke Pines, FL; D. Hurley, Medical Research South, LLC, Charleston, SC; E. Morawski, Holston Medical Group, Kingsport, TN; R. Cherlin, Richard Cherlin, MD, Los Gatos, CA; V. Houchin, Harrisburg Family Medical Center, Harrisburg, AR; M. Welch, D. Goytia-Leos, Consano Clinical Research, San Antonio, TX; M. Syed, Ilumina Clinical Associates, Indiana, PA; E. Kowaloff, L. Weinrauch, Atlantic Clinical Trials, LLC, Watertown, MA; J. Peniston, Avington Memorial Hospital, Feasterville Trevose, PA; A. Brockmyre, Holston Medical Group, Bristol, TN; B. First, Ritchken & First MD's, San Diegeo, CA; L. Feld, Horizon Clinical Research Associates, Gilbert, AZ; D. Huffman, University Diabetes & Endocrine Consultants, Inc, Chattanooga, TN; O. Nassim, Clinical Research, Inc, Huntington Park, CA; G. Gottschlich, New Horizons Clinical Research, Cincinnati, OH; A. Patel, C. Knopke, Integrated Research Group, Inc, Riverside, CA; M. Hernandez, Berma Research Group, Hialeah, FL; J. Diaz, The Community Research of South Florida, Hialeah, FL; G. Giugliano, J. Nicasio, Baystate Medical Center, Springfield, MA; D. Eagerton, Carolina Health Specialists, Myrtle Beach, SC; R. Huntley, Norwalk Medical, Norwalk, CT; J. Reed, III, Endocrine Research Solutions, Inc, Roswell, GA; M. Magee, MedStar Health Research Institute, Washington, DC; R. Hippert, Integrated Medical Group PC, Fleetwood, PA; C. Sofley, Jr., Internal Medicine Associates of Anderson, PA, Anderson, SC; O. Alzohaili, Alzohaili Medical Consultants, Dearborn, MI; P. Levins, R. Anspach, Clinical Research Advantage, Inc, Phoenix, AZ; S. Shah, St. Joseph's Medical Associates, Stockton, CA; O. Brusco, Osvaldo Brusco, MD, Corpus Christi, TX; J. Naidu, Naidu Clinic, Odessa, TX; J. Lindenbaum, Jeffry Lindenbaum DO, PC, Yardley, PA; R. Jacks, Hill County Medical Associates, New Braunfels, TX; G. Hammond, Dormir Clinical Trials, Inc, Midvale, UT; C. Arena, Utah Clinical Trials, LLC, Salt Lake City, UT; K. Saxman, Oregon Medical Group Adult Medicine Clinic, Eugene, OR; M. Mach, Valley Endocrine & Diabetes Consultants, Inc, Valencia, CA; H. Kerstein, Howard Kerstein, MD, Denver, CO; D. Kereiakes, The Carl and Edyth Linder Center For Research and Education, Cincinnati, OH; J. Wahlen, Advanced Research Institute, South Ogden, UT; K. Wehmeier, UF Endocrinology & Diabetes, Jacksonville, FL; L. Chaykin, Meriden Research, Bradenton, FL; J. Rothman, University Physicians Group, Staten Island, NY; L. Fogelfeld, John H. Stroger Jr, Hospital of Cook County, Chicago, IL; N. Bittar, Gemini Scientific, LLC, Madison, WI; J. Rosenstock, Dallas Diabetes and Endocrine Center, Dallas, TX; D. Kayne, Medical Group of Encino, Encino, CA; J. Navarro, Genesis Clinical Research, Tampa, FL; H. Colfer, Nisus Research, Petoskey, MI; S. Mokshagundam, Robley Rex VA Medical Center, Louisville, KY; L. Shandilya, Ettrick Health Center, PA, South Chesterfield, VA; L. Connery, Lion Research, Norman, OK; C. Wysham, Rockwood Diabetes and Metabolic Health Center, Spokane, WA; A. Dela Llana, MediSphere Medical Research Center, LLC, Evansville, IN; M. Jardula, Desert Oasis Healthcare, Palm Springs, CA; M. MacAdams, Lubbock Diagnostic Clinic, Lubbock, TX; G. Flippo, Alabama Clinical Therapeutics, LLC, Birmingham, AL; E. Heurich, C. Curtis, Compass Research, Orlando, FL; D. Sanders, R. Rawls, Horizan Research Group, Inc, Mobile, AL; F. Velazquez, Pioneer Research Solutions, Inc, Houston, TX; E. Osea, Innovative Clinical Research, Inc, Harbor City, CA; K. Mahood, Family Medicine of Sayebrook, Myrtle Beach, SC; G. Feldman, South Carolina Pharmaceutical Research, Spartanburg, SC; F. Eder, United Medical Associates, Binghamton, NY; E. Riley, IV, W. Fowler, Tower Pointe Research Center, Hodges, SC; M. Jain, Southwest Clinical Research Centers, LLC, Pearland, TX; M. Shepard, Medstar Research Institute, Hyattsville, MD; M. Schear, Dayton Clinical Research, Dayton, OH; B. Barker, Delaware Research, Delaware, OH; C. Strout, Coastal Carolina Research Center, Mt. Pleasant, SC; O. Obiekwe, Ropheka Medical Center, Riverdale, GA; M. Shanik, Endocrine Associates of Long Island, PC, Smithtown, NY; C. Green, E. Blakney, The Green Clinic PC, Memphis, TN; K. Roberson, Delta Waves, Inc., Colorado Springs, CO; E. Bretton, Albuquerque Clinical Trials, Albuquerque, NM; R. Pish, Pish Medical Associates, Uniontown, PA; K. Kaveh, Coastal Nephrology Associates Research Center, LLC, Port Charlotte, FL; B. Maynard, W. Barager, R. Soldyshev, Great Falls Clinic, LLP, Great Falls, MT; B. Austin, Preferred Primary Care Physicians, Inc, Pittsburgh, PA; P. Parmar, R. Simpson, The Lynn Institute, Denver, CO; A. Chauhan, Prime Medicial Group, Clairton, PA; J. Kasper, R. Burr, Focus Clinical Research, Draper, UT; N. Patel, Wells Institute for Health Awareness, Kettering, OH; H. Mariano, Research Center of Fresno, Inc, Fresno, CA; T. Pluto, Fay West Family Practice, Scottdale, PA; C. Bratcher, Diabetes America at Plano, Plano, TX; M. Juarez, Panacea Clinical Research, San Antonio, TX; L. Levinson, Tipton Medical & Diagnostic Center, Tipton, PA; A. Awad, Clinical Research Consultants, LLC, Kansas City, MO; K. Longshaw, Leading Edge Research, PA, Dallas, TX; K. Hoffman, TRY Research, Maitland, FL; R. Richwine, Texas Health Physicians Group, Fort Worth, TX; D. Molter, North Myrtle Beach Family Practice, North Myrtle Beach, SC; J. Boscia, III, CU Pharmaceutical Research, Union, SC; S. Kowalyk, Endocrinolgy Associates, Greensburg, PA; P. Lemis, Jefferson Cardiology Association, Clairton, PA; J. Liss, Medical Research & Health Education Foundation Inc, Columbus, GA; R. Orr, Phoenix Medical Group, PC, Peoria, AZ; J. Riser, Riser Medical Research, Picayune, MS; J. Wood, Leading Edge Research, PA/INOVA, Richardson, TX; A. Ubani, Windsor Medical Clinic, Tampa, FL; W. Paine, F. Hassani, Mileground Family Practice, Morgantown, WV; F. Miranda, Dr. Francisco Miranda, Miami, FL; V. Hansen, Val R. Hansen, MD, Bountiful, UT; N. Farris, The Research Group of Lexington, LLC, Lexington, KY; R. Bowden, Charleston Internal Medicine Research Institute, Charleston, Charleston, WV; D. Ajani, Southwest Clinical Trial, Houston, TX; K. Maw, J. Andersen, Meridien Research, Brooksville, FL; B. Bergman, Benefis Health Group, Great Falls, MT; S. Dunmyer, Pharmacotherapy Research Associates, Inc, Zanesville, OH; D. Brandon, California Research Foundation, San Diego, CA; M. Anderson, Kernodle Clinic, Burlington, NC; P. Bononi, Partners in Nephrology & Endocrinology, Pittsburgh, PA; J. Prawer, Joel Prawer, MD, Saint Petersburg, FL; B. Seidman, Seidman Clinical Trials, Delray Beach, FL; H. Cruz, Florida Institute for Clinical Research, Orlando, FL; K. Wilks, Kerri Wilks, MD; Hallandale Beach, FL; L. DiSanto, Lisa DiSanto, DO, Saint Petersburg, FL; R. Buynak, Buynak Clinical Research, Valparaiso, IN; T. Christensen, Calabash Medical Center, Calabash, NC; P. Denker, Gulfcoast Endocrine and Diabetes Center, Clearwater, FL; W. Koppel, Walter Koppel, MD, Towson, MD; M. Stedman, Stedman Clinical Trials, Tampa, FL; L. Lewy-Alterbaum, All Medical Research LLC, Cooper City, FL; S. Karim, J. Shapiro, Philadelphia Health Associates, Philadelphia, PA; T. Gardner, T. Oskin, Northside Internal Medicine, Spokane, WA; N. Gabra, J. Malano, Burke Internal Medicine & Research, Burke, VA.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2018010103/-/DCSupplemental.
- Copyright © 2018 by the American Society of Nephrology
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