Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events

Study Oversight

The trial was approved by the ethics committee at each participating center, and all participants provided written informed consent. The study was sponsored by Novartis Pharma, was designed by the sponsor in collaboration with an academic executive committee, and was monitored by an independent data and safety monitoring committee (see Supplementary Appendix 1, available with the full text of this article at NEJM.org).¹¹ Data were collected, managed, and analyzed by the sponsor, with oversight by the executive committee, and analyses were replicated by an independent academic statistician from the London School of Hygiene and Tropical Medicine. The manuscript was prepared by the writing group (see Section 1 in Supplementary Appendix 1), whose members had unrestricted access to the data, and was revised subsequently by all the authors. All the authors made the decision to submit the manuscript for publication and assume responsibility for the accuracy and completeness of the data. The NAVIGATOR trial protocol is available in Supplementary Appendix 2.

Study Participants

Subjects were eligible for inclusion in the study if they had impaired glucose tolerance,³ a fasting plasma glucose concentration of at least 95 mg per deciliter (5.3 mmol per liter) but less than 126 mg per deciliter (7.0 mmol per liter), and one or more cardiovascular risk factors (in the case of subjects who were 55 years of age or older) or known cardiovascular disease (in the case of subjects who were 50 years of age or older) (Section 2 in Supplementary Appendix 1). Subjects were excluded if they had abnormal laboratory test results or concomitant conditions that could interfere with the assessment of the safety or efficacy of the study drug or if they had taken antidiabetic medication within the previous 5 years.¹¹

Study Medication

Participants were randomly assigned, with the use of an interactive voice-response telephone system, to nateglinide, at a dose of 60 mg taken before meals three times daily, or placebo and, in a 2-by-2 factorial design, to valsartan or placebo. Both the participants and the investigators were unaware of the treatment assignments. Nateglinide was initially dispensed at a dose of 30 mg, with an increase to the full dose of 60 mg after 2 weeks. Reductions in the dose were permitted if there were side effects. The comparison of valsartan with placebo is reported elsewhere in this issue of the Journal.¹²

Lifestyle Modification

All subjects were required to participate in a study-specific lifestyle modification program that was designed to reduce the risk of diabetes (see Section 3 in Supplementary Appendix 1). The aim of the program was to help participants achieve and maintain a 5% weight loss, reduce the amount of saturated and total fats in their diets, and increase their physical activity to 150 minutes weekly.^5,6 To facilitate adherence, site personnel who were trained to administer the program provided materials to participants at each clinic visit and reinforcement through interim telephone contacts.

Study Procedures

After the dose-adjustment phase, participants returned for study visits every 6 months. The fasting plasma glucose level was measured every 6 months for 3 years and annually thereafter. Oral glucose-tolerance tests were performed yearly. On the mornings of study visits, the administration of the study medication was delayed until after the glucose tests had been performed so that the glucose measurements would not be affected by the study drugs.

Study Outcomes

Initially, there were two coprimary outcomes: incident diabetes mellitus and an extended composite cardiovascular outcome (death from a cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina). A third coprimary core cardiovascular outcome (death from a cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), which had initially been designated as a secondary outcome, was added, as described previously.^11,13

Diabetes was considered to be present^14,15 if the participant had a fasting plasma glucose level of 126 mg per deciliter or more or a glucose level of 200 mg per deciliter (11.1 mmol per liter) or more 2 hours after a glucose challenge — confirmed by an oral glucose-tolerance test within 12 weeks after the elevated glucose value was recorded. The date of the onset of diabetes was considered to be the date of the first elevated glucose value. An independent committee, whose members were unaware of the treatment assignments, adjudicated cases in which diabetes was diagnosed by other means. Participants in whom diabetes developed could have open-label antidiabetic medication — with the exception of prandial glucose regulators — added to their regimen.

Deaths, hospitalizations, and potential cardiovascular events that did not result in hospitalization were adjudicated by an independent committee whose members were unaware of the treatment assignments. (Definitions of these outcomes are provided in Section 4 in Supplementary Appendix 1.)

Statistical Analysis

The targeted sample size of 9152 participants was determined on the basis of the estimated number of participants that would be needed to provide the power required for the valsartan-versus-placebo component of the study.^11,13 We estimated that diabetes would develop in at least 3000 of these participants, with the result that the study would have more than 99% power to detect a 25% reduction in the risk of incident diabetes.

Since the effects of the two drugs (nateglinide and valsartan) on the three coprimary outcomes were examined in a factorial manner, we adjusted for the three tests that were performed for each drug, but not across drugs. We report two-sided P values throughout, as well as protocol-specified one-sided values for the coprimary outcomes and their components. The 2.5% one-sided family-wise type I error rate for each drug was controlled with the use of a closed-testing procedure that initially assigned one fifth of the alpha to the diabetes outcome and four fifths to the two cardiovascular outcomes (since we anticipated that there would be more cases of diabetes than of cardiovascular outcomes). This allowed for the testing of each coprimary outcome even if the others did not differ significantly between the study groups but would usually require a two-sided P value of less than 0.01 for the difference in the diabetes outcome to be considered significant (Section 5 in Supplementary Appendix 1). An O'Brien–Fleming type of alpha spending approach accounted for the interim efficacy analysis that was performed in November 2005, when 30% of the target number of participants had had an extended cardiovascular outcome (one-sided alpha spent: 0.00004).¹⁶

Log-rank tests, stratified according to the presence or absence of a history of cardiovascular disease and to randomized assignment to valsartan or placebo, were used to compare the nateglinide and placebo groups with respect to the time to the first event in the extended or core cardiovascular outcome. A Cox discrete-time proportional-odds model¹⁷ was used to assess incident diabetes, given the fixed-time schedule for glucose measurements. We also performed predefined analyses of the components of the composite cardiovascular outcome, exploratory outcomes (the time to death from all causes and the time to cardiovascular-related hospitalization), indexes of hyperglycemia, and body weight. We tested for a possible interaction between valsartan and nateglinide for each reported outcome. The effects of the study treatment were evaluated in prespecified subgroups (Section 6 in Supplementary Appendix 1).¹¹ Baseline characteristics of the participants, safety assessments, and additional measurements during the trial were compared with the use of summary statistics.

Study Participants

Figure 1. Figure 1. Enrollment and Follow-up of Study Participants.

Of 43,502 participants who were screened at 806 centers in 40 countries, 9518 were randomly assigned to a study drug between January 4, 2002, and January 29, 2004. The most common reasons for exclusion were ineligibility (96.6%) and refusal to participate (2.5%). After randomization, 212 participants at 10 sites were excluded when the sites were closed owing to deficiencies in the adherence to Good Clinical Practice guidelines, leaving 9306 participants whose data were included in the final analyses (Figure 1).

Among participants who were taking the study drug at 6 months, fewer people in the nateglinide group than in the placebo group were taking the full dose of the study drug (92.0% vs. 94.2%, P<0.001). At 1 year, 79.8% of the surviving participants in the nateglinide group and 80.8% of those in the placebo group were still receiving the study medication (P=0.26); the respective percentages were 74.7% and 75.9% at 3 years (P=0.20) and 69.9% and 71.0% at 5 years (P=0.28).

Table 1. Table 1. Baseline Characteristics of the Trial Participants According to the Assigned Study Medication.

The baseline characteristics of the nateglinide and placebo groups did not differ significantly (Table 1). Of the 9306 participants, 3547 (38.1%) reported that a primary relative had diabetes and 2266 (24.3%) had known cardiovascular disease. There were no significant differences between the groups in concomitant treatments at baseline or at study end. At study end, less than 3% of the participants in whom diabetes had not developed were taking open-label glucose-lowering therapies.

Follow-up

The fasting plasma glucose level or the plasma glucose level 2 hours after a glucose challenge was measured at the closeout visit or during the final 6 months of the study in 80% of the surviving participants who had not withdrawn consent and in whom diabetes had not developed. A total of 609 participants in the nateglinide group (13.1%) and 602 in the placebo group (12.9%) were lost to follow-up or withdrew from the study; however, because many of these participants were lost to follow-up or withdrew consent late in the study, information on vital status was available for 95.7% of the possible follow-up time in both groups. The median follow-up time for data on vital status was 6.5 years, and the median follow-up times for data on the diabetes, extended cardiovascular, and core cardiovascular outcomes were 5.0, 6.3, and 6.4 years, respectively.

Study Outcomes

Coprimary Diabetes Outcome

Table 2. Table 2. Rates of Coprimary Outcomes, Component Events, and Key Exploratory Outcomes.

Figure 2. Figure 2. Kaplan–Meier Curves for the Coprimary and Two Exploratory Outcomes in the Nateglinide and Placebo Groups.

Panel A shows results for the coprimary outcome of incident diabetes, Panel B for the coprimary outcome of extended cardiovascular outcomes (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, heart failure, or arterial revascularization), Panel C for the coprimary outcome of core cardiovascular outcomes (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), and Panel D for death from any cause and death from cardiovascular causes. All P values are one-sided except for those for exploratory outcomes, which are two-sided. I bars indicate 95% confidence intervals.

Diabetes developed in 1674 participants in the nateglinide group (36.0%) and in 1580 participants in the placebo group (33.9%) (hazard ratio with nateglinide, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05) (Table 2 and Figure 2A). The effect of nateglinide on the progression of impaired glucose tolerance to diabetes was consistent across all prespecified subgroups except for subgroups specified according to sex and fasting plasma glucose level (Section 6A in Supplementary Appendix 1).

Coprimary Cardiovascular Outcomes

The extended composite cardiovascular outcome occurred in 658 participants in the nateglinide group (14.2%) and in 707 participants in the placebo group (15.2%) (hazard ratio with nateglinide, 0.93; 95% CI, 0.83 to 1.03; P=0.16 (Table 2 and Figure 2B). The core composite cardiovascular outcome occurred in 365 participants in the nateglinide group (7.9%) and in 387 participants in the placebo group (8.3%) (hazard ratio with nateglinide, 0.94; 95% CI, 0.82 to 1.09; P=0.43) (Table 2 and Figure 2C). Nateglinide treatment had no significant effect on the coprimary cardiovascular outcomes in any of the prespecified subgroups (Sections 6B and 6C in Supplementary Appendix 1).

Components of Primary Outcomes and Exploratory Outcomes

As shown in Table 2 and Figure 2D, there were no significant differences between the nateglinide and placebo groups with respect to the components of the extended cardiovascular composite outcome, including death from cardiovascular causes, or with respect to the prespecified exploratory outcomes of hospitalization for a cardiovascular cause and death from any cause.

No interactions between nateglinide and valsartan were seen for any of the outcomes reported (Section 7 in Supplementary Appendix 1).

Glycemia

Figure 3. Figure 3. Changes in Mean Plasma Glucose Levels, Weight, Waist Circumference, and Blood Pressure in the Nateglinide and Placebo Groups over the Course of the Study.

To convert the values for glucose to milligrams per deciliter, divide by 0.05551. I bars indicate standard errors.

During the course of the study, participants in the nateglinide group had lower mean fasting plasma glucose levels than did those in the placebo group; the mean difference was 0.47 mg per deciliter (95% CI, 0.05 to 0.90) (0.03 mmol per liter [95% CI, 0.003 to 0.05]) (P=0.03) (Figure 3A). However, glucose levels 2 hours after a glucose challenge were higher in the nateglinide group than in the placebo group; the mean difference was 4.37 mg per deciliter (95% CI, 2.80 to 5.93) (0.24 mmol per liter [95% CI, 0.16 to 0.33]) (P<0.001) (Figure 3B).

In the two exploratory analyses we conducted, incident diabetes defined on the basis of fasting plasma glucose levels and adjudicated outcomes alone occurred in 775 of the participants in the nateglinide group (16.7%) and 877 of the participants in the placebo group (18.8%) (hazard ratio with nateglinide, 0.87; 95% CI, 0.79 to 0.96; P=0.005). In contrast, incident diabetes defined on the basis of plasma glucose levels 2 hours after a glucose challenge and adjudicated outcomes alone occurred in 981 of the participants in the nateglinide group (21.1%) and 819 of the participants in the placebo group (17.6%) (hazard ratio with nateglinide, 1.24; 95% CI, 1.13 to 1.36; P<0.001). Mean (±SD) glycated hemoglobin levels, measured at the time the diagnosis of diabetes was made, were lower in the nateglinide group than in the placebo group (6.1±0.6% vs. 6.3±0.6%, P<0.001).

Weight and Blood Pressure

There was a reduction in mean body weight during the study, with 10.1% of participants losing 5% of their baseline weight by 6 months, but the mean body weight was higher among participants in the nateglinide group than among those in the placebo group throughout the course of the study (mean difference, 0.35 kg; 95% CI, 0.22 to 0.48; P<0.001) (Figure 3C). Mean waist circumference was also higher in the nateglinide group than in the placebo group (Figure 3D). No significant between-group differences were seen in systolic or diastolic blood pressure (Figure 3E and 3F).

Adverse Events and Discontinuation of the Study Drug

A total of 520 participants in the nateglinide group (11.2%) and 485 in the placebo group (10.4%) discontinued the study drug owing to an adverse event (P=0.23). Rates of adverse events did not differ significantly between the groups, except that more participants in the nateglinide group reported hypoglycemia (mostly mild events) (911 participants [19.6%], vs. 527 [11.3%] in the placebo group; P<0.001) (Section 8 in Supplementary Appendix 1).

In our study, the addition of nateglinide therapy to a lifestyle modification program did not reduce the risk of diabetes or cardiovascular events among subjects with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors. In two large-scale studies of lifestyle intervention, the rate of progression from impaired glucose tolerance to diabetes was reduced by 58%.^5,6 Some pharmacologic interventions have also reduced the risk of diabetes: in the 3.3-year Study to Prevent Non–Insulin-Dependent Diabetes Mellitus (STOP-NIDDM; ClinicalTrials.gov number, NCT00629213), there was a 25% relative risk reduction with the alpha glucosidase inhibitor acarbose⁷; in the 2.8-year Diabetes Prevention Program (DPP; NCT00004992), there was a 31% reduction with the biguanide metformin⁶; and in the 3-year Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study (NCT00095654), there was a 62% reduction with the thiazolidinedione rosiglitazone.⁸ The prevention or delay of diabetes with lifestyle intervention or metformin therapy can persist for up to 10 years.²⁰ However, a 3-year study of the second-generation sulfonylurea gliclazide, a long-acting insulin secretagogue, did not show any reduction in the progression from fasting hyperglycemia to diabetes.²¹ In addition, no reduction was seen with the first-generation sulfonylurea tolbutamide in an intention-to-treat analysis of the 10-year follow-up data from the Malmöhus trial.²²

The D-phenylalanine derivative nateglinide is a short-acting insulin secretagogue. When it is taken before meals, it reduces postprandial glucose excursions (i.e., increases above the premeal value) by enhancing early insulin secretion.²³ It was hypothesized that nateglinide might reduce the risk of progression to diabetes by restoring a more physiologic insulin response to meals than that which occurs with sulfonylureas such as glyburide.²⁴ In addition, by diminishing postprandial hyperglycemia, nateglinide could have a favorable effect on the risk of cardiovascular events, given the independent significant association between elevated glucose levels after a glucose challenge and cardiovascular disease,² and given the reduced risk of myocardial infarction seen in the STOP-NIDDM trial.¹⁰ We found that nateglinide offers no protection from the progression of impaired glucose tolerance to diabetes or from the progression of cardiovascular disease, and possibly raises glucose levels after a glucose challenge. A trial evaluating the effect of acarbose, an insulin-sparing agent, on cardiovascular outcomes among patients with impaired glucose tolerance and cardiovascular disease is under way.²⁵

In a pilot study, glucose values 2 hours after a glucose challenge were significantly reduced when nateglinide was taken immediately before the test.²² In the NAVIGATOR study, in which the study medication was withheld on mornings before oral glucose-tolerance testing, we observed elevated glucose values 2 hours after a glucose challenge. It is uncertain whether these elevated values reflect the immediate effect of withdrawal of nateglinide, which may be similar to the immediate effect of withdrawal of gliclazide,²¹ or a long-term diminution in the beta-cell response to an acute glucose challenge. The former may be the case, since a 7-day study in which subjects ate a standardized test meal showed that postprandial glucose levels did not rebound above baseline values on the day that nateglinide was withdrawn.²⁶ In addition, glycated hemoglobin levels that were measured when diabetes developed were lower in the nateglinide group than in the placebo group, suggesting that the higher glucose values 2 hours after a glucose challenge that were seen after withdrawal of nateglinide may be a short-term rather than a long-term effect. Further interpretation might be aided by the assessment of markers of beta-cell function or insulin resistance, but peptide levels were not assayed, and samples from oral glucose-tolerance tests were not retained.

The lifestyle modification program seems to have had an effect, as evidenced by the weight loss in both study groups, but the mean body weight in the nateglinide group was 0.35 kg higher than that in the placebo group. The lower mean weight loss with nateglinide could be associated with a greater risk of diabetes, given the findings of the Diabetes Prevention Program, in which there was a 58% reduction in the risk of diabetes among the lifestyle-intervention subjects, who achieved a 5% weight loss over the course of 3 years⁶; however, formal modeling would be required to test this hypothesis.

Concerns about potential adverse cardiovascular effects of glucose-lowering agents, particularly in persons with cardiovascular disease or at high risk for cardiovascular disease, have led the Food and Drug Administration to require cardiovascular-outcome studies for new antidiabetic agents.²⁷ In this respect, nateglinide appears to be safe in persons with impaired glucose tolerance, although the risk of hypoglycemia is increased.

The results of the NAVIGATOR trial show that among persons with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors, assignment to nateglinide, at a dose of 60 mg three times daily, as compared with placebo, in addition to a lifestyle modification program, did not reduce the incidence of diabetes or cardiovascular outcomes.

The authors are as follows: Rury R. Holman, M.B., Ch.B., F.R.C.P., Steven M. Haffner, M.D., John J. McMurray, M.B., Ch.B., M.D., M. Angelyn Bethel, M.D., Björn Holzhauer, Dipl.Math., Tsushung A. Hua, Ph.D., Yuri Belenkov, M.D., Ph.D., Mitradev Boolell, M.D., John B. Buse, M.D., Ph.D., Brendan M. Buckley, M.D., D.Phil., Antonio R. Chacra, M.D., Ph.D., Fu-Tien Chiang, M.D., Bernard Charbonnel, M.D., Chun-Chung Chow, M.B., B.S., Melanie J. Davies, M.B., Ch.B., M.D., Prakash Deedwania, M.D., Peter Diem, M.D., Daniel Einhorn, M.D., Vivian Fonseca, M.D., Gregory R. Fulcher, M.B., B.S., M.D., Zbigniew Gaciong, M.D., Ph.D., Sonia Gaztambide, M.D., Ph.D., Thomas Giles, M.D., Edward Horton, M.D., Hasan Ilkova, M.D., Trond Jenssen, M.D., Steven E. Kahn, M.B., Ch.B., Henry Krum, M.D., Ph.D., Markku Laakso, M.D., Ph.D., Lawrence A. Leiter, M.D., Naomi S. Levitt, M.D., Viacheslav Mareev, M.D., Ph.D., Felipe Martinez, M.D., Chantal Masson, R.N., Theodore Mazzone, M.D., Eduardo Meaney, M.D., Ph.D., Richard Nesto, M.D., Changyu Pan, M.D., Rudolf Prager, M.D., Sotirios A. Raptis, M.D., Ph.D., Guy E.H.M. Rutten, M.D., Ph.D., Herbert Sandstroem, M.D., Frank Schaper, M.D., Andre Scheen, M.D., Ph.D., Ole Schmitz, M.D., Isaac Sinay, M.D., Vladimir Soska, M.D., Steen Stender, M.D., Gyula Tamás, M.D., Ph.D., Gianni Tognoni, M.D., Jaako Tuomilehto, M.D., Ph.D., Alberto S. Villamil, M.D., Juraj Vozár, M.D., Ph.D., and Robert M. Califf, M.D.

The affiliations of the authors are as follows: Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford (R.R.H, M.A.B.); the British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow (J.J.M.); and the Department of Cardiovascular Sciences, University of Leicester, Leicester (M.J.D.) — all in the United Kingdom; University of Texas Health Science Center, San Antonio, TX (S.M.H.); Duke Clinical Research Institute (M.A.B.) and Duke Translational Medicine Institute (R.M.C.), Duke University, Durham; and the Division of General Medicine and Clinical Epidemiology and Diabetes Care Center, University of North Carolina School of Medicine, Chapel Hill (J.B.B.) — both in North Carolina; Novartis Pharma, Basel (B.H., M. Boolell, C.M.), and the Division of Endocrinology Diabetes and Clinical Nutrition, Inselspital, University Hospital and University of Bern, Bern (P. Diem) — both in Switzerland; Novartis Pharmaceuticals, East Hanover, NJ (T.A.H.); Lomonosov Moscow State University, Moscow (Y.B., V.M.); University College Cork, Cork, Ireland (B.M.B.); Federal University of São Paulo, São Paulo (A.R.C.); Department of Cardiology, National Taiwan University Hospital, Taipei, Taiwan (F.-T.C.); Endocrinology Department, University Hospital, Nantes, France (B.C.); the Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong (C.-C.C.); and Department of Endocrinology, 301 Hospital, Beijing. (C.P.) — both in China ; the Division of Cardiology, University of California–San Francisco Program at Fresno, and the Veterans Affairs (VA) Central California Health Care System, Fresno (P. Deedwania); and the University of California–San Diego and Scripps Whittier Diabetes Institute, La Jolla (D.E.) — all in California; the Endocrinology Department (V.F.) and the Heart and Vascular Institute (T.G.), Tulane University School of Medicine, New Orleans; Royal North Shore Hospital, University of Sydney, NSW (G.R.F.); and the Clinical Pharmacology Unit, Department of Epidemiology and Preventive Medicine, Monash University–Alfred Hospital, Prahan, VIC (H.K.) — both in Australia; Department of Internal Medicine, Hypertension, and Vascular Diseases, Warsaw Medical University, Warsaw, Poland (Z.G.); Department of Endocrinology, Hospital Universitario de Cruces, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barakaldo, Spain (S.G.); Joslin Diabetes Center, Boston (E.H.); Department of Endocrinology, Diabetes, and Metabolism, Internal Medicine, Istanbul University, Istanbul, Turkey (H.I.); Oslo University Hospital Rikshospitalet, Oslo Institute of Clinical Medicine, and the University of Tromsø, Tromsø — all in Norway (T.J.); VA Puget Sound Health Care System and University of Washington, Seattle (S.E.K.); the University of Kuopio and Kuopio University Hospital, Kuopio (M.L.); and Hjelt Institute, Department of Public Health, Helsinki University, Helsinki, and South Ostrobothnia Central Hospital, Seinajoki (J.T.) — all in Finland; Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Endocrine Unit, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa (N.S.L.); Cordoba National University, Cordoba (F.M.); and Instituto Cardiovascular de Buenos Aires (I.S.) and Hypertension Unit, Division of Cardiology, Argerich Hospital, University of Buenos Aires (A.S.V.), Buenos Aires — all in Argentina; Department of Diabetes and Metabolism, University of Illinois, Chicago (T.M.); Hospital 1o de Octubre Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Federal District, Mexico City, Mexico (E.M.); Lahey Clinic, Burlington, MA (R.N.); Hietzig Hospital (Krankenhaus Hietzing mit Neurologischen Zentrum Rosenhügel), Vienna (R.P.); Second Department of Internal Medicine, Endocrinology and Diabetology, Attikon University Hospital, Hellenic National Diabetes Center, Athens (S.A.R.); Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands (G.E.H.M.R.); Family Medicine, Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden (H.S.); Center for Clinical Studies, Metabolism, and Endocrinology–Knowledge and Technology Transfer of Dresden University of Technology, Dresden, Germany (F.S.); Division of Diabetes and Clinical Pharmacology Unit, Centre Hospitalier Universitaire de Liège, University of Liege, Liege, Belgium (A.S.); Medical Department M–Endocrinology and Diabetes, Århus University Hospital, and Department of Clinical Pharmacology, Århus University, Århus (O.S.); and Department of Clinical Biochemistry, Gentofte Hospital, University of Copenhagen, Copenghagen (S.S.) — both in Denmark; Department of Clinical Biochemistry and Second Clinic of Internal Medicine, Faculty Hospital of St. Anna, Brno, Czech Republic (V.S.); 1st Department of Medicine, Diabetes Unit, Semmelweis University, Budapest, Hungary (G. Tamás); Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy (G. Tognoni); and Diabetologic Outpatient Clinic, Jesenius Samaria, Šamorín, Slovak Republic (J.V.).