GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

The incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide contribute to glucose-stimulated insulin release and therefore play important roles in maintaining normal glucose regulation (1). In type 2 diabetes, the incretin effect is impaired (2,3), but it remains controversial to what extent the defect is caused by a reduced release of incretin hormones and whether this reduction occurs prior to the development of type 2 diabetes. Systematic reviews and meta-analyses have found that GLP-1 release is generally unaltered in type 2 diabetes (4,5). However, single studies have found a reduced (6,7) or even upregulated (8) GLP-1 response to oral glucose in patients with type 2 diabetes, indicating variation among subsets of populations with type 2 diabetes. Information obtained from individuals with prediabetes may contribute to a better understanding of the timing of a potential alteration in GLP-1 response in type 2 diabetes pathogenesis. In this context, reduced GLP-1 response to oral glucose has been documented in individuals with impaired glucose tolerance (IGT) (9–11) and impaired fasting glucose (IFG) (9), although elevated GLP-1 concentrations have also been found in a small group of individuals with IFG (12).

Part of the diversity in the GLP-1 response to oral glucose in previous studies may be related to varying diabetes duration and severity of diabetes of the studied patients, both of which are associated with alterations in GLP-1 response (7,11). Moreover, long-term use of metformin or dipeptidyl peptidase-4 inhibitors could have disturbed the natural pattern of GLP-1 release by changing proglucagon expression in the L cells (13). Other explanations for the inconsistency in study findings are different distributions of age, sex, and obesity, which cannot be sufficiently accounted for in small studies with few study participants. BMI has been inversely associated with GLP-1 response in a number of studies (7,11,14,15). However, only a few studies have observed or studied sex differences in the GLP-1 response to glucose (3,11), possibly due to low number of study participants. Generally, women have lower fasting but higher 2-h glucose concentrations (16,17), slower gastric emptying (18) and glucose absorption rates (19), and higher insulin sensitivity (20) than men. Therefore, it is also likely that the release of GLP-1 in response to oral glucose ingestion differs between men and women.

We measured the plasma concentrations of GLP-1 during an oral glucose tolerance test (OGTT) in a large population of individuals with normal glucose tolerance (NGT), prediabetes, or screen-detected type 2 diabetes and in normal weight, overweight, and obese individuals. Furthermore, we studied whether the plasma GLP-1 response was related to age, sex, insulin sensitivity, and β-cell function.

The study participants were from the ADDITION-PRO study, a longitudinal risk-stratified cohort study of individuals at high risk for developing type 2 diabetes, nested in the ADDITION-Denmark study. After participation in a population-based step-wise screening program in Danish general practice (ADDITION-Denmark: 2001–2006) (21), 22,200 individuals with impaired glucose regulation or NGT but elevated diabetes risk and 13,288 individuals with low diabetes risk were identified. In 2009, 16,136 of these were eligible for reinvitation based on criteria described previously (21). Individuals with impaired glucose regulation at screening and individuals from a random subsample of individuals at lower diabetes risk were invited to a follow-up health examination (2009–2011), and 2,082 participants (50% of those invited) attended (22).

The study was approved by the ethics committee of the Central Denmark Region (reference no. 20080229) and was conducted in accordance with the Helsinki Declaration. All participants provided oral and written informed consent before participating in the study.

At the examination in 2009–2011, participants without known diabetes were given a standard 75-g OGTT after an overnight fast of ≥8 h. Blood samples were drawn at 0, 30, and 120 min for assessment of serum insulin, plasma glucose, and plasma GLP-1 concentrations. In addition, HbA_1c was measured.

Information on age and sex was obtained from the unique Danish civil registration number. Body weight was measured with participants wearing light indoor clothing without shoes to the nearest 0.1 kg with a Tanita Body Composition Analyzer (Tanita, Tokyo, Japan). Height was measured to the nearest millimeter using a fixed rigid stadiometer (Seca; Medical Scales and Measuring Systems, Hamburg, Germany). Clothes were estimated to weigh 0.5 kg, which was deducted from the total body weight, and BMI was calculated. Waist circumference was measured with an unyielding tape measure to the nearest millimeter at the midpoint between the lower costal margin and the anterior superior iliac crest. The ADDITION-PRO study has previously been described in detail (22).

All study participants were classified according to the World Health Organization 2006 criteria as having NGT (fasting glucose <6.1 mmol/L and 2-h glucose <7.8 mmol/L), isolated IFG (i-IFG) (6.1 mmol/L ≤ fasting glucose < 7.0 mmol/L and 2-h glucose <7.8 mmol/L), isolated IGT (i-IGT) (fasting glucose <6.1 mmol/L and 7.8 mmol/L ≤ 2-h glucose < 11.1 mmol/L), combined IFG and IGT (IFG&IGT) (6.1 mmol/L ≤ fasting glucose < 7.0 mmol/L and 7.8 mmol/L ≤ 2-h glucose < 11.1 mmol/L), or screen-detected type 2 diabetes (fasting glucose ≥7.0 mmol/L or 2-h glucose ≥11.1 mmol/L). Prediabetes was defined as having i-IFG, i-IGT, or IFG&IGT.

Participants with known diabetes (n = 336), those fasting <8 h prior to the health examination (n = 20), those who could not be classified owing to missing information on fasting or 2-h plasma glucose concentrations (n = 12), and those with no blood samples taken for measurement of GLP-1 (n = 252) were excluded, leaving 1,462 individuals for analysis. For analysis of associations with obesity, the 1,462 participants were classified according to BMI as normal weight (BMI <25 kg/m²), overweight (25 kg/m² ≤ BMI < 30 kg/m²), or obese (BMI ≥30 kg/m²).

Blood samples for measurement of GLP-1 were taken in tubes containing EDTA and put on ice immediately, centrifuged for plasma content, and stored at −80 degrees. Radioimmunological determinations of total plasma GLP-1 concentration [intact GLP-1 plus the metabolite GLP-1-(9-36)amide] were performed as described previously (23–25). The analytical detection limit was 1 pmol/L, and intra- and interassay coefficients of variation were 6.0% and 1.5%, respectively, at GLP-1 plasma concentrations of 20 pmol/L. The samples were analyzed consecutively during 2 months using identical quality controls and identical batches for all reagents in each analysis set.

Concentrations of plasma glucose and serum insulin were measured at Steno Diabetes Center. Plasma glucose was determined using the Hitachi 912 system (Roche Diagnostics, Mannheim, Germany) or the Vitros 5600 system (Ortho Clinical Diagnostics, Illkirch Cedex, France). Based on validation analysis performed at the laboratory at Steno Diabetes Center, all Vitros values (71% of all) were converted to Hitachi values using the following equation: adjusted value = (original glucose value + 0.2637)/0.983. There was a high correlation between original and converted values (r² = 0.997). Serum insulin was measured by immunoassay (AutoDELFIA; Perkin Elmer, Waltham, MA). The intra- and interassay coefficients of variation were 0.011 and 0.036, respectively, at serum insulin concentrations of 129 pmol/L. HbA_1c was measured by high-performance liquid chromatography (TOSOH G7, Tokyo, Japan).

Total areas under the curve (tAUCs) from the basal state to 30 and 120 min for glucose, insulin, and GLP-1 were calculated using the trapezoid rule. We calculated the relative early response (rAUC_0–30) as tAUC_0–30/(fasting concentration × 30 min) and the relative full response (rAUC_0–120) as tAUC_0–120/(fasting concentration × 120 min). As a proxy measure of overall insulin sensitivity, we calculated the insulin sensitivity index (ISI_0–120) (26). The insulinogenic index, calculated as (insulin_{30 min} − insulin_{0 min})/(glucose_{30 min} − glucose_{0 min}), was used as a surrogate measure of first-phase insulin release (27). Thirty participants had slightly negative values for this index. These values were changed to an arbitrary value close to zero (0.01) in the subsequent analysis. We also estimated a disposition index (DI) by multiplying the insulinogenic index by ISI_0–120.

Data on insulin, GLP-1, ISI_0–120, insulinogenic index, and DI were logarithmically transformed before analysis to fulfill the requirement of normal distribution of the residuals. The data are presented as means (SD) for normally distributed variables and geometric means (95% CIs) for non–normally distributed variables.

To examine differences in characteristics between glucose tolerance groups or BMI groups, we performed an overall ANOVA and, if significant, pairwise differences were studied with post hoc t tests. Test of differences in total and relative responses of glucose, insulin, and GLP-1 between glucose tolerance groups were adjusted for age, sex, and BMI.

Test of differences in total and relative responses of GLP-1 between BMI groups were adjusted for age, sex, and glucose tolerance status. Sex differences were adjusted for age and BMI and tested with Student t test. Associations of rAUC_0–30 and rAUC_0–120 for GLP-1 with insulinogenic index, ISI_0–120, DI, age, BMI, and waist circumference were studied by linear regression analyses. We tested for a modifying effect of sex on the associations. Analyses were adjusted for age, sex, glucose tolerance status, and BMI (when relevant).

Statistical analyses were performed in R, version 3.0.2 (The R Foundation for Statistical Computing), and SAS, version 9.2 (SAS Institute, Cary, NC). A two-sided 5% level of significance was used for all analyses.

Compared with the NGT group, the group with i-IGT was older, and the groups with i-IFG and screen-detected type 2 diabetes had a lower proportion of women (Table 1). The i-IFG and i-IGT groups were more overweight than those with NGT but less overweight than the IFG&IGT group and the group with screen-detected type 2 diabetes. HbA_1c levels were progressively higher with worsening of glucose tolerance.

Circulating concentrations of glucose and insulin are shown in Table 2 for women and Table 3 for men. Per definition, fasting and 2-h glucose levels differed between groups, and the same was true for total and relative AUCs for glucose (Table 2; Table 3; Fig. 1A and D). Fasting and 2-h insulin concentrations as well as total insulin responses during the OGTT were also higher in men and women with prediabetes or type 2 diabetes compared with NGT individuals (Table 2; Table 3; Fig. 1B and E).

In women, 120-min GLP-1 concentrations were 20% lower in IFG&IGT and type 2 diabetes compared with the NGT group (Table 2). Early (rAUC_0–30) and full (rAUC_0–120) relative GLP-1 responses were 18–25% lower in women with prediabetes compared with NGT women both before and after adjustment for age and BMI (Table 2; Fig. 1F). In men, 120 min GLP-1 concentrations were 16% lower in IFG&IGT and 13% lower in type 2 diabetes compared with NGT after adjustment for age and BMI, whereas the relative GLP-1 release during the OGTT did not differ by glucose tolerance status (Table 3; Fig. 1C). Comparable results were found when the incremental AUC was calculated instead of rAUC (Supplementary Table 1).

In general, men had higher fasting GLP-1 concentrations than women, whereas women had higher 30- and 120-min GLP-1 concentrations and total and relative GLP-1 responses than men (Supplementary Table 2). Because women in general have a smaller body size than men, we also adjusted the analyses of sex differences for body weight or height instead of BMI. Adjustment for body weight made the sex differences in fasting plasma glucose and GLP-1 levels nonsignificant (P = 0.921 and P = 0.161, respectively), but differences in GLP-1 response to oral glucose did not disappear after weight adjustment. Adjustment for height did not change any of the results presented in Supplementary Table 2.

Both early and full relative GLP-1 responses (rAUC_0–30 and rAUC_0–120) were decreased by 20% in obesity and eight percent in overweight compared with normal weight after adjustment for age, sex and glucose tolerance status (Fig. 2). Comparable results were obtained when using the incremental AUC for GLP-1 (Supplementary Fig. 1).

There was a significant and positive correlation between the relative change in plasma GLP-1 and glucose concentrations 30 min after oral glucose ingestion but with a very small effect size; a doubling of rAUC_0–30 for GLP-1 was associated with a 1% increase in rAUC_0–30 for glucose (Fig. 3A). We also found a sex difference in the relationship; for the same relative change in GLP-1 concentrations, women had a significantly lower plasma glucose response. A doubling in rAUC_0–30 GLP-1 was associated with a 18% increase in insulin rAUC_0–30 (Fig. 3B). There was no correlation between rAUC_0–120 for GLP-1 and rAUC_0–120 for glucose (Fig. 3C), but a doubling of rAUC_0–120 GLP-1 was associated with a 10% increase in rAUC_0–120 insulin (Fig. 3D). The GLP-1 and insulin correlations did not differ by sex.

Both rAUC_0–30 and rAUC_0–120 were significantly and positively associated with all three markers of glucose metabolism and with no differences between men and women. A doubling of rAUC_0–30 GLP-1 was associated with a 23% increase in insulinogenic index (Fig. 4A), a 4% increase in ISI_0–120 (Fig. 4B), and a 28% increase in DI (Fig. 4C). Similarly, a doubling of rAUC_0–120 GLP-1 was associated with a 20% increase in insulinogenic index (Fig. 4D), a 4% increase in ISI_0–120 (Fig. 4E), and a 24% increase in DI (Fig. 4F).

Fig. 5 illustrates the relationships of rAUC_0–30 and rAUC_0–120 for GLP-1 with age, BMI, and waist circumference. Sex did not modify the associations (P_interaction ≥0.3 for all). A 5-year increase in age was associated with 3% higher rAUC_0–30 and rAUC_0–120 for GLP-1 (Fig. 5A and D); however, for a given age the relative GLP-1 response was higher in women than in men. In contrast to age, higher BMI or waist circumference was associated with lower relative GLP-1 response to the oral glucose load; a three-unit increase in BMI was associated with a 4–6% decrease in rAUC_0–30 and rAUC_0–120 for GLP-1 (Fig. 5B and E) and a ten-cm increase in waist circumference was associated with a 4–7% decrease in rAUC_0–30 and rAUC_0–120 for GLP-1 (Fig. 5C and F). For a given obesity degree, women had a higher GLP-1 response than men.

It has been controversial whether the impaired incretin effect observed in type 2 diabetes and obesity may result from a reduction in the release of incretin hormones and, if so, whether this reduction occurs prior to the development of type 2 diabetes and obesity (4–8,28,29). A general belief has been that impaired GLP-1 release in overt type 2 diabetes and obesity is a phenomenon secondary to other metabolic abnormalities (4,30). However, findings of reduced GLP-1 release in individuals with prediabetes have questioned this hypothesis (9–12), which is further supported by a high heritability of the GLP-1 response to oral glucose (3,31,32).

Our results, based on a large study population of 1,462 Danish adults, demonstrate that GLP-1 responses to an OGTT are up to 25% impaired in prediabetes and type 2 diabetes compared with NGT individuals and most pronounced in women compared with men. Furthermore, independent of glucose tolerance status, obese and overweight individuals had up to 20% impaired GLP-1 response compared with normal weight individuals. These findings indicate that alterations in incretin hormone release contribute to glucose and appetite dysregulation rather than being a consequence of type 2 diabetes or obesity. We also show that the early GLP-1 response was positively related to insulin sensitivity, β-cell function, and age but inversely associated with BMI and waist circumference in both sexes and that women in general had higher GLP-1 response than men.

Our finding of a lower GLP-1 response in prediabetes and screen-detected type 2 diabetes in women is in agreement with previous studies of response to an OGTT in men and women with i-IGT, IFG&IGT, and type 2 diabetes (6,9–12). Differences in circulating GLP-1 levels were particularly observed after 120 min, which supports previous observations of reduced late GLP-1 response in diabetes and prediabetes (11). Among women, rAUC for GLP-1 was lower in prediabetes, but not in screen-detected diabetes, compared with the NGT group, which may suggest that a compensatory increase in GLP-1 release takes place with worsening of glucose tolerance above the prediabetic range. If this assumption is correct, the threshold for a compensatory increase in GLP-1 seems to be lower for men than for women, since a slight but not significant increase in rAUC for GLP-1 was observed in men with IFG&IGT but not in men with screen-detected diabetes. Such a compensatory mechanism could also explain why some studies find increased GLP-1 release in patients with newly diagnosed type 2 diabetes (29) and others find reduced GLP-1 release in patients who are already in treatment for type 2 diabetes (7). A review and meta-analysis including a total of 400 individuals receiving oral glucose or a meal test showed that patients with type 2 diabetes and individuals without diabetes overall have similar GLP-1 responses (4). Another meta-analysis combining data from 22 trials during 29 different stimulation tests concluded the same (5). However, collecting data from smaller studies obtained by different stimulation tests performed on diverse patient and control groups with different distribution of sex, age, and BMI makes interpretations difficult. In addition, different analytical methods may also influence the results. We now demonstrate, in the largest study to date, that GLP-1 responses to oral glucose are affected by sex, glucose tolerance status, age, and BMI. This may explain the diverse results obtained in previously published studies, where a small number of study participants made such detailed analysis impossible.

BMI has been inversely associated with GLP-1 response in a number of studies (7,11,14,15,31). We have now confirmed in a large cohort of individuals with normal and impaired glucose regulation that obesity, independent of glucose tolerance, is an important determinant of GLP-1 release.

Glucose-stimulated GLP-1 levels were positively associated with first-phase insulin release, insulin sensitivity, and the DI. These findings are in agreement with the glucoregulatory effects of GLP-1 (33,34) and with studies showing that infusion of the GLP-1 receptor antagonist exendin-(9-39) reduced first-phase insulin release and decreased insulin action in healthy individuals and in patients with type 2 diabetes (35,36). GLP-1 has also been shown to expand the microvascular surface area of skeletal muscles and may therefore improve the metabolic action of insulin (37). However, our finding that doubling of the GLP-1 response was associated with an up to 28% increase in the insulinogenic index and the DI, but only with a 4% increase in insulin sensitivity, underscores that the ability of GLP-1 to improve β-cell response is more predominant than the ability of GLP-1 to improve insulin sensitivity, which is in agreement with previous observations (38).

Some of the mechanisms behind the lower GLP-1 response in both prediabetes and overweight may include genetic variation in the regulation of GLP-1 synthesis (3,31,32,39), since twin studies have shown that GLP-1 response has a heritability of up to 67% (31). Lower GLP-1 response has also been observed in the twin with diabetes of twin pairs discordant for type 2 diabetes (3). Finally, the L cells may be sensitive to insulin resistance, since weight loss, and thereby reduction of insulin resistance, induces a marked increase in GLP-1 release (40).

Sex differences in the secretion of GLP-1 have not been studied in detail because of small and selected study populations. As women have lower fasting plasma glucose concentrations (16,17), higher 2-h plasma glucose concentrations (16,17), slower gastric emptying (18) and glucose absorption rates (19), and higher insulin sensitivity (20) than men, we chose to analyze our study population stratified by sex. Indeed, we found that the lower GLP-1 response in prediabetes and type 2 diabetes was most pronounced in women. However, this finding was partially due to the result of ∼20% higher relative GLP-1 response in normoglycemic women than in their male counterparts, whereas the GLP-1 response in men and women with prediabetes or type 2 diabetes was comparable in absolute terms. Therefore, our results suggest that healthy women have a higher GLP-1 response than men, but when glucose tolerance is worsening, this sex difference is no longer apparent.

The role of age in the release of GLP-1 has not previously been clearly established (4,41). Our finding of a significantly positive association between age and GLP-1 response in the entire study population may reflect a general reduced renal clearance with increasing age, thereby increasing the GLP-1 concentration (42). It should be noted, however, that the effect size was rather small; a 5-year increase in age was associated with a 3% increase in GLP-1 response.

The main strength of this study is the large cohort with NGT, prediabetes, and screen-detected type 2 diabetes. We had the opportunity to examine individuals with screen-detected/epidemiological and, hence, untreated diabetes, which is not possible in studies based on clinically known diabetes cases. It is well documented that prediabetes, and especially IFG&IGT, is associated with a high risk for developing type 2 diabetes (43), and therefore we conclude that the changes in GLP-1 response observed in individuals with i-IFG, i-IGT, and IFG&IGT precede the development of overt type 2 diabetes, at least in women. Our finding of a relationship of GLP-1 release with insulin sensitivity, β-cell function, BMI, and waist circumference supports this notion. It should also be mentioned that any reduced GLP-1 response observed in our study population can reflect either an impaired release or an increased elimination of GLP-1 (44). However, as other studies have found similar elimination rates and gastric emptying rates of GLP-1 in individuals with and without diabetes (45,46), our findings of reduced GLP-1 response in prediabetes and diabetes are likely to reflect an impaired release of GLP-1.

The GLP-1 response to 75-g oral glucose may be considered less physiologically relevant than a mixed-meal test. However, it is more difficult to standardize a mixed-meal test than an OGTT, and differences in GLP-1 response between individuals with and without diabetes seem to be more pronounced after a solid meal compared with an OGTT (5). Accordingly, confirmation of our findings in large studies using mixed-meal tests is important in terms of generalizability and application of the results to clinical practice.

We used a well-documented assay method with high specificity and sensitivity for analyzing the plasma samples (24,25). Many studies of GLP-1 secretion have been carried out with various commercially available kits, which have considerable variation in specificity and sensitivity. This should be taken into account for assay selection and when comparing data from different studies (47). Another important aspect of the measurement method is that we measured total GLP-1 and not active (intact) GLP-1. The reason for choosing this method is that measurement of total GLP-1 provides information not only about the release of GLP-1 but also about its probable biological effects. In contrast, measurement of peripheral circulating levels of the intact GLP-1 metabolite [GLP-1-(9-36)NH₂/37] only reflects the small fraction of the hormone that reaches its targets via the classical endocrine route (possibly as little as 8% of what was released [48]) after having exerted part of its action via the nervous system (49). Due to the large number of study participants, samples were only collected at three time points during the OGTT. However, since the response of GLP-1 to oral glucose has been shown to peak around 30 min independent of the degree of dysglycemia (8,12,32) the estimated AUCs are likely to include the peak GLP-1 response.

Some individuals have lower plasma GLP-1 levels after 120 min than in the fasting state. Accordingly, calculation of the incremental AUC will result in negative numbers and therefore be missing after log transformation. In our data set, 5% of data would be missing if the incremental AUC were used instead of the relative AUC for GLP-1, and most of the missing variables were in the smaller groups with prediabetes and diabetes. The relative and incremental AUCs express the same (the change in GLP-1 release from baseline) but on a different scale (relative vs. absolute).

In the largest study population analyzed to date, comprising 1,462 individuals, we demonstrate that GLP-1 response to an OGTT is up to 25% impaired in prediabetes and screen-detected diabetes compared with NGT and most pronounced in women compared with men. Furthermore, independent of glucose tolerance status, obese and overweight individuals had up to 20% impaired GLP-1 response compared with normal weight individuals. Thus, we now show that a reduction in GLP-1 release occurs already before diabetes or obesity is manifest. This finding indicates that alterations in GLP-1 release contribute to dysregulation of glucose metabolism and appetite rather than being a consequence of type 2 diabetes or obesity.

Treatment with GLP-1 analogs has been shown to induce weight loss and reverse prediabetes to NGT (50–52). Since we found reduced endogenous GLP-1 levels and response in prediabetes, treatment with GLP-1 analogs could be relevant as part of a prevention strategy if weight loss attempts are unsuccessful, in agreement with recent findings from studies of obese individuals with prediabetes (50,51,53).

Acknowledgments. The authors acknowledge the ADDITION-PRO study centers, the staff, and the participants for their important contribution to the study. The authors thank the laboratory technicians Lene Albæk and Sofie P. Olesen, University of Copenhagen.

Funding. The ADDITION-Denmark study was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe, and Southern Jutland in Denmark; the Danish Council for Strategic Research; the Danish Research Foundation for General Practice; Novo Nordisk Foundation; the Danish Centre for Evaluation and Health Technology Assessment; the Diabetes Fund of the National Board of Health; the Danish Medical Research Council; the Aarhus University Research Foundation; and the Danish Council for Strategic Research. The ADDITION-PRO study was funded by an unrestricted grant from the European Foundation for the Study of Diabetes/Pfizer for Research into cardiovascular disease risk reduction in patients with diabetes (74550801). N.B.J. is funded by the Danish Diabetes Academy, supported by the Novo Nordisk Foundation. T.L. has received unrestricted grants for the ADDITION study from public foundations.

Duality of Interest. The ADDITION-PRO study received internal research and equipment funds from Steno Diabetes Center A/S, a research hospital working in the Danish National Health Service and owned by Novo Nordisk A/S. Steno Diabetes Center receives part of its core funding from unrestricted grants from the Novo Nordisk Foundation and Novo Nordisk. K.F., D.V., N.B.J., and M.E.J. are employed by Steno Diabetes Center A/S. K.F., S.S.T., D.V., N.B.J., D.R.W., O.P., T.L., and M.E.J. hold shares in Novo Nordisk A/S. T.L. has received unrestricted grants between 2000 and 2011 for the ADDITION study (screening and intensive treatment of type 2 diabetes in primary care) from the medical industry: Novo Nordisk AS, Novo Nordisk Scandinavia AB, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, SERVIER Denmark A/S, and HemoCue Denmark A/S. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. K.F. and S.S.T. drafted the manuscript. K.F., S.S.T., D.V., and N.B.J. researched and interpreted data. D.V. performed the statistical analyses. N.B.J., D.R.W., T.L., and A.S. designed the ADDITION-PRO study. K.F., S.S.T., D.V., N.B.J., D.R.W., A.J., O.P., T.H., T.L., A.S., J.J.H., and M.E.J. contributed to interpretation of data, revised the manuscript critically, and approved the final version of manuscript. S.S.T. and J.J.H. generated GLP-1 data. K.F. 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. Parts of this study were presented in abstract form at the 74th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 13–17 June 2014.