Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes

Metformin is the recommended first-line pharmacological treatment for type 2 diabetes (1). Metformin acts mainly by reducing hepatic glucose production via inhibition of gluconeogenesis (2,3) and also increases glucose uptake in peripheral tissue (3). Metformin is associated with a low risk of hypoglycemia and is weight neutral or can lead to weight loss (1). However, as type 2 diabetes progresses, metformin monotherapy often fails to maintain glycemic control (1,4). In such cases, there is often a failure to intensify treatment as appropriate (5). In a retrospective cohort study of more than 81,000 patients with type 2 diabetes, the median time to the addition of another oral glucose-lowering agent after a patient exceeded his or her HbA_1c target ranged from 1.6 to 2.9 years (6). The reasons for this clinical inertia are unclear but likely include a reluctance to initiate more complex drug regimens (7).

Initial combination therapy with oral antidiabetes drugs with complementary modes of action may provide more robust and durable glucose-lowering efficacy compared with the traditional stepwise approach (8). A combination approach to first-line treatment is recommended by the American Diabetes Association/European Association for the Study of Diabetes and the Canadian Diabetes Association for patients whose HbA_1c is ≥9% (≥75 mmol/mol) or ≥8.5% (≥69 mmol/mol), respectively (1,9).

Most of the glucose filtered by the kidney is reabsorbed by the sodium glucose cotransporter 2 (SGLT2) (10). SGLT2 inhibitors act by reducing renal glucose reabsorption, thereby increasing urinary glucose excretion and reducing hyperglycemia (10). Empagliflozin is a potent and selective SGLT2 inhibitor (11). When used as an add-on to metformin in patients with type 2 diabetes, empagliflozin (10 mg and 25 mg q.d.) significantly reduced HbA_1c, fasting plasma glucose (FPG), and weight and was well tolerated, with a low risk of hypoglycemia (12).

This study was undertaken to compare the efficacy and safety of initial combinations of empagliflozin and metformin immediate release (IR) with those of empagliflozin and metformin IR monotherapy in patients with type 2 diabetes.

This was a Phase III, randomized, double-blind, parallel-group study conducted from October 2012 to December 2014 in 190 centers in 21 countries. The clinical trial protocol and amendments were approved by the institutional review boards, independent ethics committees, and competent authorities of the participating centers and complied with the Declaration of Helsinki in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice. All subjects provided informed consent before participation.

This study enrolled adults with type 2 diabetes with BMI ≤45 kg/m² at screening who were drug-naïve (no oral antidiabetes therapy, glucagon-like peptide-1 analog, or insulin for ≥12 weeks before randomization). Before a protocol amendment, patients with HbA_1c >7% to ≤10% (>53 to ≤86 mmol/mol) at screening were eligible for randomized treatment and patients with HbA_1c >10% (>86 mmol/mol) at screening were eligible for open-label treatment. After the protocol amendment, patients with HbA_1c >7.5% to ≤12% (>58 to ≤108 mmol/mol) at screening were eligible for randomized treatment, and enrollment in the open-label arm was stopped; however, patients already enrolled in the open-label arm were allowed to complete the study. The increase in the HbA_1c inclusion threshold for randomized treatment was implemented so that the effects of initial therapy with empagliflozin + metformin in patients with high HbA_1c could be evaluated in a randomized controlled environment.

Exclusion criteria included uncontrolled hyperglycemia (plasma glucose >240 mg/dL [13.3 mmol/L] after an overnight fast during a 2-week placebo run-in, confirmed by a second measurement); contraindication to metformin according to the local label; renal impairment (estimated creatinine clearance rate <60 mL/min using the Cockcroft-Gault formula) or indication of liver disease (serum alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase >3 times the upper limit of normal) at screening or during the placebo run-in; treatment with antiobesity drugs within 3 months before consent; and any uncontrolled endocrine disorder except type 2 diabetes.

After a 2-week placebo run-in period, eligible patients were randomized (1:1:1:1:1:1:1:1) to receive empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d., empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 5 mg b.i.d. + metformin 1,000 mg b.i.d., empagliflozin 10 mg q.d., empagliflozin 25 mg q.d., metformin 500 mg b.i.d., or metformin 1,000 mg b.i.d. for 24 weeks. Patients randomized to receive metformin 1,000 mg b.i.d. underwent dose escalation: 500 mg b.i.d. in the first week, increasing to 850 mg b.i.d. in the second week and to 1,000 mg b.i.d. in the third week; dose adjustment other than this was not permitted. Patients allocated to the open-label arm received empagliflozin 12.5 mg b.i.d. + 1,000 mg b.i.d. for 24 weeks.

Randomization was achieved using a computer-generated random sequence and an interactive voice and Web response system. Randomization was stratified by the following factors: HbA_1c (<8.5% [<69 mmol/mol] and ≥8.5% [≥69 mmol/mol]) at screening, renal function (estimated glomerular filtration rate [eGFR] ≤90 mL/min/1.73m² and ≥90 mL/min/1.73m² using the Modification of Diet in Renal Disease equation) at screening, and region (Europe, Asia, North America, Latin America). Study visits were scheduled at screening, at the start of the placebo run-in, and at weeks 0 (baseline), 6, 12, 18, and 24 of treatment. A follow-up visit occurred 7 days after the last intake of study drug.

Rescue medication could be initiated if, after an overnight fast, a patient had a confirmed blood glucose level >240 mg/dL (13.3 mmol/L) between weeks 1 and 12 or >200 mg/dL (11.1 mmol/L) between weeks 12 and 24. The use of other SGLT2 inhibitors and metformin was not permitted. In cases of hypoglycemia, rescue medication was to be reduced in dose or discontinued. If hyper- or hypoglycemia could not be controlled, the subject was discontinued from the trial.

The primary end point was change from baseline in HbA_1c at week 24. Key secondary end points were changes from baseline in FPG and weight at week 24. Exploratory efficacy end points included the proportion of patients with HbA_1c ≥7% (≥53 mmol/mol) at baseline who had HbA_1c <7% (<53 mmol/mol) at week 24, the proportion of patients with HbA_1c ≥7% (≥53 mmol/mol) at baseline who had HbA_1c <6.5% (<48 mmol/mol) at week 24 (defined post hoc), the proportion of patients with >5% reduction in weight at week 24 (defined post hoc), and changes from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24.

Safety end points included clinical laboratory parameters and adverse events (AEs), with preferred terms coded according to the Medical Dictionary for Drug Regulatory Activities (MedDRA) version 17.1. AEs included all events with an onset after the first dose and up to 7 days after the last dose of trial medication. Confirmed hypoglycemic AEs, defined as AEs with plasma glucose ≤70 mg/dL (3.9 mmol/L) and/or requiring assistance, were identified by direct plasma glucose measurements and by home blood glucose monitoring performed by the patient. Other predefined AEs of special interest included events consistent with urinary tract infection (UTI), genital infection, and volume depletion, identified using prospectively defined search categories based on 67, 87, and 8 MedDRA preferred terms, respectively. AEs related to increased urination were assessed based on a post hoc search for the MedDRA preferred terms pollakiuria, polyuria, and nocturia.

The primary analysis was a restricted maximum likelihood–based mixed-model repeated-measures (MMRM) approach assessing changes from baseline in HbA_1c at week 24, with treatment, baseline renal function, region, visit, and visit by treatment as fixed effects, and baseline HbA_1c as a linear covariate. The analysis was performed on the full analysis set (FAS) (randomized patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA_1c assessment) using observed cases (OC). Values observed after a patient started glucose-lowering rescue therapy were set to missing. A sample size of 168 patients per group was required to provide power of 89% to detect a 0.5% treatment difference in HbA_1c between empagliflozin + metformin and the individual components, assuming a dropout rate of 2%.

A hierarchical testing procedure was used, beginning with a test for superiority of combination treatment versus the corresponding empagliflozin once-daily regimens and metformin twice-daily doses in change from baseline in HbA_1c at week 24. Null/alternative hypotheses were grouped into dose levels (empagliflozin 5 mg b.i.d. + metformin 1,000 mg b.i.d., empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d., and empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d.). Two hypotheses were tested within each dose level: one tested for superiority of the empagliflozin + metformin combination versus the empagliflozin component, and the other tested whether the combination was superior to the metformin component. The two hypotheses were tested simultaneously, each at the level of α = 0.05 (two-sided). If all the steps in the hierarchical testing above were successful, noninferiority testing of change from baseline in HbA_1c at week 24 with empagliflozin 25 mg q.d. versus metformin 1,000 mg b.i.d. and empagliflozin 10 mg q.d. versus metformin 1,000 mg b.i.d. was to be performed at the level of α = 0.025 (one-sided). If all the steps in the noninferiority testing were successful, then change from baseline to week 24 in FPG and then change from baseline to week 24 in weight (combination treatment vs. metformin twice daily only) were to be analyzed using the same hierarchical testing procedure as for the primary analysis. The baseline value for the end point in question was included as a linear covariate.

Sensitivity analyses of the primary end point were performed using the per protocol set (patients in the FAS without important protocol violations) and FAS completers (patients in the FAS who completed 23 ± 1 weeks’ treatment); the same model as for the primary analysis was used. The primary end point at week 24 was also analyzed in the FAS (last observation carried forward) using an ANCOVA model with treatment, baseline renal function, and region as fixed effects and baseline HbA_1c as a linear covariate. Categorical changes in HbA_1c were analyzed using logistic regression in the FAS with noncompleters considered failure imputation.

Efficacy analyses in the open-label group were descriptive and based on OC.

Safety and lipid parameters were analyzed in the treated set (patients who received ≥1 dose of study drug) and were descriptive.

Of 1,364 patients who were randomized, 1,327 were treated and had a baseline and one or more on-treatment HbA_1c value, comprising the FAS. Overall, 90.8% of patients who were randomized and treated completed the treatment period. Baseline characteristics were balanced across the randomized treatment groups (Table 1). An additional 53 patients with HbA_1c >10% (>86 mmol/mol) were treated with open-label empagliflozin 12.5 mg b.i.d. + 1,000 mg b.i.d., and 49 (92.5%) completed the treatment period (Supplementary Fig. 1).

At week 24, pronounced reductions from baseline in HbA_1c (mean baseline 8.55–8.86% [70–73 mmol/mol]) were observed in all randomized treatment groups (Fig. 1A). Compared with empagliflozin once-daily regimens, the adjusted mean differences in changes from baseline with empagliflozin + metformin twice daily ranged from −0.57 to −0.72% (−6.2 to −7.9 mmol/mol; P < 0.001) and compared with metformin twice daily ranged from −0.33 to −0.79% (−3.6 to −8.6 mmol/mol; P < 0.001). Adjusted mean HbA_1c over the treatment period is shown in Fig. 1B. At week 24, adjusted mean HbA_1c values with empagliflozin + metformin twice daily ranged from 6.6% (49 mmol/mol) with empagliflozin 5 mg b.i.d. or 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. to 6.7% (50 mmol/mol) with empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d. Values were 7.3% (57 mmol/mol) and 7.3% (56 mmol/mol) for empagliflozin 10 mg q.d. and 25 mg q.d., respectively, and 7.5% (58 mmol/mol) and 6.9% (52 mmol/mol) for metformin 500 mg and 1,000 mg b.i.d., respectively (Fig. 1B). The results of sensitivity analyses of changes in HbA_1c were consistent with the primary analysis (Supplementary Table 1). Significantly greater proportions of randomized patients with HbA_1c ≥7% (≥53 mmol/mol) at baseline reached HbA_1c <7% (<53 mmol/mol) and HbA_1c <6.5% (<48 mmol/mol) at week 24 with empagliflozin + metformin twice daily than with empagliflozin once daily or metformin twice daily (Fig. 1C and Supplementary Fig 2). Empagliflozin did not achieve noninferiority versus metformin 1,000 mg b.i.d. in changes from baseline in HbA_1c at week 24 (adjusted mean difference vs. metformin 1,000 mg b.i.d.: empagliflozin 25 mg, 0.39% [4.3 mmol/mol], P = 0.625; empagliflozin 10 mg, 0.40% [4.4 mmol/mol], P = 0.656). Owing to failed noninferiority testing in the hierarchical sequence, the subsequent analyses for FPG and weight are considered exploratory.

In the randomized treatment groups, empagliflozin + metformin twice daily significantly reduced FPG compared with empagliflozin once-daily and metformin twice-daily regimens at week 24 (Supplementary Fig 3A). Adjusted mean differences in changes from baseline with empagliflozin + metformin twice-daily compared with empagliflozin once-daily regimens ranged from −0.7 to −1.3 mmol/L (P < 0.001; nonconfirmatory) and compared with metformin twice-daily regimens ranged from −0.9 to −1.6 mmol/L (P < 0.001). Adjusted mean FPG over the treatment period is shown in Supplementary Fig 3B.

Rescue medication was taken by one patient (0.6%) in each of the groups on empagliflozin + metformin twice daily compared with six (3.7%) on empagliflozin 25 mg q.d., three (1.8%) on empagliflozin 10 mg q.d., seven (4.3%) on metformin 1,000 mg b.i.d., and nine (5.4%) on metformin 500 mg b.i.d.

In the randomized treatment groups, there was a pronounced change from baseline in weight at week 24 with empagliflozin + metformin twice-daily regimens (range −2.8 to −3.8 kg) that appeared to be additive, given the changes in weight observed with empagliflozin once daily (−2.4 kg for both regimens) and the small changes observed with metformin twice-daily regimens (range −0.5 to −1.3 kg) (Fig. 2A). Adjusted mean differences in changes from baseline with empagliflozin + metformin twice-daily regimens compared with metformin twice-daily regimens ranged from −2.2 to −2.5 kg (P < 0.001; nonconfirmatory). Adjusted mean weight over the treatment period is shown in Fig. 2B. A significantly greater proportion of patients achieved a >5% reduction in weight with empagliflozin + metformin twice-daily than with metformin twice-daily regimens at week 24 (Fig. 2C).

Changes from baseline in BP at week 24 in the randomized treatment groups are reported in Supplementary Table 2. Reductions from baseline in SBP (mean baseline 126.3 mmHg) at week 24 ranged from −2.2 to −3.2 mmHg with empagliflozin + metformin twice-daily regimens, −2.1 to −2.3 mmHg with empagliflozin once-daily regimens, and −0.2 to 0.8 mmHg with metformin twice-daily regimens. Empagliflozin + metformin twice daily significantly reduced SBP compared with metformin twice daily but not compared with empagliflozin once-daily regimens; adjusted mean differences in changes from baseline with empagliflozin + metformin twice daily compared with metformin twice daily ranged from −2.8 to −4.0 mmHg (P < 0.05). Reductions from baseline in DBP (mean baseline 78.2–79.4 mmHg) at week 24 ranged from −1.6 to −1.9 mmHg with empagliflozin + metformin twice daily, −1.0 to −1.7 mmHg with empagliflozin once daily, and 0 to 0.6 mmHg with metformin twice-daily regimens. Empagliflozin + metformin twice daily significantly reduced DBP compared with metformin twice daily but not compared with empagliflozin once-daily regimens. The adjusted mean differences in changes from baseline with empagliflozin + metformin twice daily compared with metformin twice daily ranged from −1.9 to −2.3 mmHg (P < 0.05).

HbA_1c over 24 weeks in the open-label treatment group (empagliflozin 12.5 mg b.i.d. + 1,000 mg b.i.d.) is shown in Fig. 1D. Mean HbA_1c was reduced from 11.5% (102 mmol/mol) at baseline to 6.7% (50 mmol/mol) at week 24. At week 24, 52.8% of patients in the open-label treatment group had HbA_1c <7%. Four (7.5%) patients in the open-label treatment group received glucose-lowering rescue medication.

The proportion of randomized patients with one or more AE was similar across all randomized treatment groups (Table 2), and 95% of randomized patients with one or more AE reported only events of mild or moderate intensity. Similar proportions of patients discontinued because of AEs across the randomized treatment groups. No patients died. The proportion of patients with confirmed hypoglycemic AEs was low in all randomized treatment groups (0–1.8%).

Events consistent with UTI were reported in 5.9–12.4% of patients across the randomized treatment groups (Table 2) and were reported in a greater proportion of female patients (12.9–23.0%) than male patients (0.0–5.6%) in all groups. None of these events led to hospitalization. Two cases of acute pyelonephritis were reported: one in the empagliflozin 5 mg b.i.d. + metformin 1,000 mg b.i.d. group and one in the empagliflozin 25 mg q.d. group; both events were mild in intensity, were resolved with antibiotics, and did not lead to hospitalization or discontinuation of study drug. Chronic pyelonephritis was reported in one patient in the metformin 500 mg b.i.d. group; this event was mild in intensity and did not lead to discontinuation of study drug. Events consistent with genital infection were reported in 1.8–6.4% of patients across the randomized treatment groups (Table 2) and were reported in a greater proportion of female patients (1.5–8.2%) than in male patients (0.0–6.0%). The proportion of patients with increased urination and volume depletion was low across the randomized treatment groups (Table 2). There were no episodes of diabetic ketoacidosis.

Laboratory measurements are presented in Supplementary Table 3. Hematocrit increased from baseline in patients treated with combination therapy or empagliflozin and decreased in patients treated with metformin. Uric acid levels decreased in the combination therapy and empagliflozin groups and increased in the metformin groups. No pattern was observed in changes in eGFR. Small increases in total cholesterol and HDL cholesterol were observed in all treatment groups, except for small decreases in total cholesterol with empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. and metformin 1,000 mg b.i.d. Small increases in LDL cholesterol were observed with empagliflozin and with empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d. but not in other groups. Triglycerides increased with empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 25 mg q.d., and metformin twice daily and decreased in all other treatment groups. There were no clinically relevant changes in electrolytes in any treatment group.

In the open-label treatment group, one patient (1.9%) had a confirmed hypoglycemic AE. No confirmed hypoglycemic events required assistance or led to study discontinuation. One patient (1.9%) had an event consistent with UTI, and two patients (3.8%) had an event consistent with genital infection. Volume depletion (hypotension) occurred in one patient (1.9%) (Table 2).

Our study found initial combinations of empagliflozin and metformin IR given twice daily for 24 weeks in patients with type 2 diabetes led to statistically significant and clinically meaningful reductions in HbA_1c compared with the corresponding empagliflozin once-daily and metformin twice-daily regimens. In the combination therapy groups, changes in HbA_1c of ∼2% were observed at week 24, irrespective of the dose of empagliflozin or metformin. The results of sensitivity analyses of changes in HbA_1c were consistent with the primary analysis and supported the robustness of the results.

Empagliflozin + metformin combinations could be a useful treatment regimen to provide rapid, clinically relevant improvements in glycemic control in newly diagnosed patients with type 2 diabetes. Importantly, 57–70% of patients with HbA_1c ≥7% at baseline who received combination therapy reached HbA_1c <7% (<53 mmol/mol) at week 24, and 37–52% reached HbA_1c <6.5%. Even in very poorly controlled patients with type 2 diabetes (mean HbA_1c of 11.5% at baseline in the open-label group), 53% reached HbA_1c <7% (<53 mmol/mol) at week 24, suggesting that an initial combination of empagliflozin and metformin may provide substantial benefits in this patient population.

High-dose metformin IR is known to be efficacious in drug-naïve patients with high baseline HbA_1c (13,14), and in this study, noninferiority of empagliflozin 25 mg and 10 mg q.d. compared with metformin 1,000 mg b.i.d. in reducing HbA_1c was not demonstrated. However, metformin is commonly associated with gastrointestinal AEs (14,15), and in practice, many patients cannot tolerate metformin at a dose of 1,000 mg b.i.d.

Many antidiabetes treatments are associated with weight gain (1), which can affect patients’ satisfaction with and adherence to treatment (16,17). Significant and clinically meaningful reductions in weight were observed with combinations of empagliflozin and metformin compared with metformin regimens, and 26–41% of patients on empagliflozin + metformin combinations had a ≥5% reduction in weight at week 24. Further, changes in weight over time suggested that maximum weight loss for empagliflozin + metformin 1,000 mg b.i.d. may not have been reached by week 24. The weight loss observed with SGLT2 inhibitors is primarily caused by loss of calories as a result of urinary glucose excretion (18) and reflects loss of both visceral and subcutaneous fat (19). In this study, the effects of empagliflozin and metformin on weight appeared to be additive, but the lack of a placebo arm means that this cannot be conclusively assessed.

Our study observed significant reductions in SBP and DBP from baseline at week 24 with empagliflozin + metformin combinations compared with metformin regimens but not compared with empagliflozin alone. This was as expected given that empagliflozin has consistently been shown to reduce BP in patients with type 2 diabetes (20). The mechanisms behind reductions in BP with empagliflozin have not been fully clarified but may reflect weight loss, volume contraction secondary to osmotic diuresis, or arterial stiffness (21–23).

The results of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial showed that in patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced cardiovascular death, hospitalization for heart failure, and all-cause mortality (24). These findings may encourage earlier use of combinations including empagliflozin in patients with type 2 diabetes and high cardiovascular risk.

All of the treatment regimens used in this study were well tolerated. The risk of hypoglycemia is an important consideration in the management of patients with type 2 diabetes because it can be dangerous and lead to reduced treatment adherence and impairment in health-related quality of life (17,25). The proportion of patients in this study with confirmed hypoglycemic AEs was low, and none required assistance. Patients with type 2 diabetes are at increased risk of UTIs and genital infections (26,27). In the current study, 5.9–12.4% of patients reported events consistent with UTI, and 1.8–6.4% of patients reported events consistent with genital infection across the randomized treatment groups. Overall, the safety profiles of the empagliflozin and metformin twice-daily combinations were consistent with the known safety profiles for empagliflozin and metformin.

In conclusion, twice-daily combinations of empagliflozin and metformin for 24 weeks led to pronounced reductions in HbA_1c and weight loss, with 57–70% of patients reaching HbA_1c <7% and 26–41% achieving weight loss of >5% at week 24. These data suggest that the initial combination of empagliflozin and metformin could represent a valuable treatment option for newly diagnosed patients with type 2 diabetes, particularly those with HbA_1c >8.5%, irrespective of the dose of metformin that a patient can tolerate.

Acknowledgments. The authors are grateful to Melanie Stephens and Wendy Morris of Fleishman-Hillard Group, Ltd. for medical writing assistance.

Duality of Interest. S.H. has served as a consultant and/or on advisory panels for AstraZeneca/Bristol-Myers Squibb, has received honoraria or speaking fees from AstraZeneca/Bristol-Myers Squibb, Abbott, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier, and Takeda, has received research grants from Abbott and Takeda, and has received travel grants from Janssen, AstraZeneca/Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi. J.R. has served on scientific advisory boards and received honoraria or consulting fees from companies involved in the development of SGLT2 inhibitors, including Bristol-Myers Squibb, AstraZeneca, Janssen, Merck, Boehringer Ingelheim, Eli Lilly, and Lexicon, and has received grants/research support from Pfizer, Merck, Bristol-Myers Squibb, AstraZeneca, Janssen, Boehringer Ingelheim, Eli Lilly, and Lexicon. T.M., H.J.W., and U.C.B. are employees of Boehringer Ingelheim. Medical writing assistance was supported financially by Boehringer Ingelheim. This study was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. No other potential conflicts of interest relevant to this article were reported.

The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version.

The authors received no financial compensation for the writing of this manuscript.

Author Contributions. S.H. contributed to the acquisition and interpretation of data and writing of the manuscript. J.R. contributed to the interpretation of data and writing of the manuscript. T.M., U.C.B., and H.J.W. contributed to the study design, interpretation of data, and writing of the manuscript. S.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Portions of the data in this study were presented at the 75th Scientific Sessions of the American Diabetes Association, Boston, MA, 5–9 June 2015 (Hadjadj S, Jelaska A, Zhang S, Meinicke T, Woerle HJ, Broedl UC et al. Diabetes 2015;64[Suppl. 1]:LB31) and at the 51st European Association for the Study of Diabetes Annual Meeting, Stockholm, Sweden, 14–18 September 2015 (Hadjadj S, Jelaska A, Zhang S, Meinicke T, Woerle HJ, Broedl UC et al. Diabetologia 2015;58[Suppl. 1]:S350).