The findings of several RWE trials support the effectiveness of dulaglutide, but to our knowledge only two of these were prospective studies [14, 15], both of which have a number of limitations, such as short duration (3–6 months) and a limited number of cases (< 200). The centers which participated in the present study have some experience in collecting real-life retrospective data , and both the European Medicines Agency and the US Food and Drug Administration have approved the use of RWE to integrate data from RCTs for regulatory decisions [17,18,19]. We became interested in conducting an independent prospective real-world observational study  on the clinical utilization of dulaglutide shortly after it became available clinical use in Italy in 2016, involving 16 different centers in Lombardy region. Our goal was to obtain a picture of the utilization of this novel once-weekly GLP-1RA that is provided with a simple auto-injector to ameliorate compliance.
The authors of a retrospective claims’ analysis including 308 adults with T2D  reported that dulaglutide was associated with a significant decrease in HbA1c levels, namely a change of 0.9%. A meta-analysis that compared the impact of dulaglutide, exenatide once weekly and liraglutide on HbA1c levels reported an absolute decrease in HbA1c at 6 months of 0.9–1.4% obtained by these GLP1-RAs . Likewise, we observed a reduction in HbA1c in our study population within 6 months of starting dulaglutide once weekly. Our findings in 1130 patients reveal a reduction in HbA1c of nearly 1.0%. Across the AWARD studies [2,3,4,5,6,7,8], dulaglutide demonstrated significant improvement of glycemic control irrespective of gender, duration of diabetes or baseline HbA1c, with greater HbA1c and FPG reductions in patients with higher baseline HbA1c. Our results also show a greater reduction in HbA1c in patients who completed 24 months of follow-up (Fig. 2a), with the greatest improvement observed in those with high HbA1c and high body weight at baseline. In a recent pooled analysis  of patients treated with dulaglutide, the reductions of HbA1c were similar across gender and among T2D subgroups according to disease duration. Our data showed that the beneficial effect of dulaglutide on glucose control (HbA1c, FPG) after 6 months persisted through the 24 months of dulaglutide therapy. In a retrospective study, Kaneko and colleagues also saw a reduction in HbA1c similar to that in our data after 24 months of dulaglutide treatment both for subjects aged ≤ 70 years and those aged > 70 years old (1.3 and 0.7%, respectively) . In REWIND , dulaglutide durably reduced HbA1c by a mean absolute amount of 0.6% more than placebo while not increasing hypoglycemia. Our population showed a mean HbA1c relative reduction of 17.8% after 12 months, and of 17.5% after 24 months, albeit starting from a baseline value higher than that reported in the REWIND study. In comparison with REWIND, our patients were younger (61.7 vs. 66.2 years), had a shorter diabetes duration (9.9 vs. 10.5 years) and had a higher BMI (33.6 vs. 32.3 kg/m2).
In our study dulaglutide therapy was associated with a significant reduction in body weight in the first 6 months of treatment. A really interesting clinical observation was that there was a significant, progressive reduction in body measurements during the study period, with weight, BMI and WC showing a gradual improvement. These observations underline the persistent efficacy of dulaglutide over time. Weight loss is correlated to a reduction in gastrointestinal motility, concomitant with a decrease in appetite and caloric intake, and to the effects of GLP-1RA on the central nervous system . Generally, the duration of diabetes and the baseline HbA1c level did not affect changes in the patients’ body weight. Similarly, we found a nearly uniform weight reduction in those who completed the 24-month follow-up regardless of their low or high HbA1c level at baseline, and independently of their low or high weight categorization (Fig. 2b). We noted a decrease in abdominal fat deposition (which correlates with visceral adiposity), as revealed by the progressive evolution of WC: − 3.3 cm after 12 months (Table 2). Such an improvement should bring metabolic benefit to our patients, as WC is positively associated with an increased risk of CV disease .
A recent retrospective, multicenter study showed that once-weekly administration of GLP-1 RA therapies may be preferable to once- or twice-daily injections because the reduction in the number of required injections could potentially increase treatment adherence and quality of life . When comparing two injectable GLP-1RAs (dulaglutide and liraglutide) to elicit patients’ preferences, dosing frequency and type of delivery system were the most important criteria, emphasizing that when differences in efficacy between medications are small, other treatment features (such as dosing frequency and delivery system) are of much greater importance to patients . As expected, patients who switched from another GLP-1RA showed a reduction in glucometabolic and anthropometric parameters to a lesser degree than did subjects who were GLP-1RA naïve (ESM Tables 4, 5). These differences can be explained by the initial beneficial effects of the previous GLP-1RA(s) prescribed to the patients, taking into account that the most important reasons to switch to dulaglutide were its once-weekly administration and its auto-injector device.
In terms of treatment persistence, few of our patients stopped using dulaglutide (14.9%) in the first year of treatment. This percentage is lower than that reported in six other RWE studies with a 6- to 12-month duration (26.2–37%) . In one study that compared patients who initiated dulaglutide, albiglutide, exenatide or liraglutide, those on dulaglutide showed a significantly higher adherence to treatment, were more treatment persistent and had lower discontinuation rates compared with those on other GLP-1RAs . In an Italian cohort study, 7319 patients with T2D who initiated exenatide, dulaglutide, liraglutide or lixisenatide were retrospectively identified in a longitudinal prescription database (retail pharmacy data) . Among the investigated treatments, the lowest persistence with therapy was among patients on exenatide twice daily and the highest persistence was among those on dulaglutide once weekly .
In our study gastrointestinal adverse events (AEs) were the main cause of discontinuation. We are aware that GLP-1 RAs are associated with gastrointestinal AEs that are related to dose and background medications (especially metformin). However, long-acting agents are known to cause less nausea and vomiting and fewer cases of diarrhea. Bettge and colleagues reported that only a small percentage (< 15%) of patients in their study discontinued dulaglutide treatment in the first year of treatment . According to a very recent observation on Chinese patients with T2D (N = 787) who were treated with dulaglutide once weekly in two phase III multicenter trials (AWARD-CHN1 and AWARD-CHN2) , most of the gastrointestinal AEs associated with dulaglutide were mild to moderate in severity; their incidence was more pronounced during the first 2 weeks of dulaglutide treatment but declined rapidly as treatment continued. Healthcare providers should take gastrointestinal-related issues into account when prescribing a GLP-1RA, but disparities between patient experiences and physician perceptions have been revealed, suggesting gaps in physician–patient communication . Unfortunately, we did not have data on the prevalence of diabetic autonomic neuropathy in our patients to better evaluate the gastrointestinal effects of dulaglutide. No cases of pancreatic cancer or acute pancreatitis in association with dulaglutide have been recorded in our clinical experience. Taking all these points into consideration, GLP-1RAs are considered to be safe drugs [33, 34].
We highlight here that the healthcare teams participating in the ANDREW study always educated each patient individually regarding MNT, physical activity in their daily living, and the correct timing of the dulaglutide injection. In a recent observation , medication adherence was low in a real-world population, particularly for GLP-1RAs, although such patients displayed the strongest weight loss benefit. The recent ADA Standard of Care  recommends selecting drug therapies that have a weight loss or weight-neutral effect for the management of T2D; consequently, overweight and obese patients should be encouraged to enhance their adherence to treatment in order to benefit the most from therapies that are associated with weight loss.
Lastly, the authors of a very recent pragmatic literature review  of 29 studies have summarized RWE for dulaglutide, suggesting that this once-weekly GLP-1RA may be associated with a clinically relevant decrease in HbA1c and a favorable therapeutic profile in routine clinical practice regarding adherence, persistence and discontinuation rates.
Limitations of the Study
A major limitation of our present study is the lack of a control group as well as the lack of data on microvascular complications and the occurrence of hypoglycemic episodes. However, ANDREW is an independent study and represents a remarkable organizational effort by healthcare centers in our region. Many meetings, webinars and conventions were arranged with the aim to share aims and data collection on clinical outcome evaluation. The diabetes care teams involved in the study (endocrinologists, internists, nurses, nutritionists, psychologists) carried out their normal daily activities, according to international and national guidelines: effective behavior management and psychological well-being should always be emphasized with any pharmacologic therapy . Recording data on the utilization of dulaglutide was an agreed-upon strategy to better understand which benefit could be valuable for our patients with T2D when prescribed a long-acting GLP-1RA injectable through a simple auto-injector device. Unfortunately, there were many missing data points in our database, both during the first year of observation but particularly during the long period. We hope to improve the precision of our data collection in the future, but fear that there will be a progressive reduction in the full completion of this large clinical study during duration of the study. Moreover, 152 patients (among 1584: 9.59%) switched to dulaglutide from another GLP-RA, and it is possible that GLP-1RA-naïve subjects will have greater benefit from the treatment than patients who switch from another drug in the same class. However, dulaglutide-naïve patients should have presented more gastrointestinal AEs than subjects who switched from another injectable incretin. A potential bias of our study is that the changes in the diabetes treatment after the initiation of dulaglutide, such as the discontinuation of SUs and the titration of insulin, could have influenced the results. These are some of the risks of a “real-world” prospective trial, performed without any grant, with no data managers, but with the best will to recommend the optimal care for our patients.