The flow of patients in the study is shown in Fig. 1. Of the 1587 patients initially screened, 1480 gave written informed consent, of which 1294 completed the study. For 64 patients, no HbA1c measurement was available for at least one of the two follow-up visits. Thus, the evaluable sample consisted of 1230 patients contributed by 314 physician-investigators.
The clinical baseline characteristics of the patients prior to the initiation of vildagliptin are given in Table 1. The mean age of the patients was 63.9 ± 10.8 years; 45.1% of the patients were aged ≥ 65 years and 58.1% were male. Mean BMI was 30.2 ± 5.6 kg/m2, mean body weight was 87.0 ± 17.0 kg and mean waist circumference was 106.9 ± 16.8 cm. The mean time since diagnosis of T2DM was 6.6 ± 5.8 years, and at the time of enrollment mean HbA1c and FPG were 8.2 ± 1.3% and 171.0 ± 53.3 mg/dL, respectively. LDL, HDL and triglycerides levels were 107.0 ± 38.2, 50.4 ± 18.8 and 180.6 ± 93.8 mg/dL, respectively. ALT and AST levels were 29.3 ± 20.3 and 34.4 ± 27.6 U/L respectively, whereas mean systolic and diastolic blood pressure were 135.2 ± 12.8 and 80.7 ± 8.4 mmHg, respectively. Many patients were diagnosed with comorbidities, of which the most prevalent were dyslipidemia (71.9%); cardiac pathology (23.2%), defined as myocardial infraction, heart failure, revascularization, etc.; renal pathology (14.1%), defined as micro-albuminuria or elevated creatinine; peripheral artery disease (12.3%); and psychiatric disorder (12.3%). The majority of patients had cardio-metabolic risk factors, such as lack of exercise (72.4%), abdominal obesity, based on physician’s judgement (71.4%), persistent high carbohydrate intake despite the diabetes diagnosis (56.6%), a family history of diabetes (39.1%) and to a lesser extent, smoking (18.3%) and excessive alcohol intake (16.3%).
The majority of the 314 physician-investigators were male (81.0%) and practicing solo (79.3%) to a mixed population of patients of all ages (82.0%). They were on average 50.9 ± 9.4 years old and had been practicing medicine for 25.5 ± 10.0 years. The median number of T2DM patients seen in the past year was 70, of whom a median of 30% had uncontrolled HbA1c (defined as having a HbA1c of > 7%). The median time spent on a first visit with a newly diagnosed T2DM patient was 20 min, whereas the median time spent on a visit for a diagnosed patient was 15 min. Physicians tended to initiate treatment at a median FPG of 126 mg/dL and a median HbA1c of 7% using primarily one or two oral agents. Most of them considered a family history of T2DM (82.5%), obesity (80.9%), dyslipidemia (75.5%) and hypertension (69.1%) as important factors influencing the decision to screen patients for T2DM. HbA1c level was considered to be the most important factor in the management of T2DM by the majority of physicians (54.5%), followed by fasting glycemia (12.4%). The following patient comorbidities were considered by the physicians as leading to a more aggressive glycemic control: hypertension (87.0%), previous cardiovascular event (82.8%), renal disease (81.2%), retinopathy by diabetes (78.0%) and hyperlipidemia (71.7%). Of the participating physicians, 38.9 and 33.4% discuss T2DM and its complications with the patient at least every 2 or 6 months, respectively, whereas 42.0 and 33.1% of them discuss the glucose-lowering medication with their patient at least every 2 or 6 months, respectively. Almost one-quarter (23.9%) of the physicians had never heard of the EASD guidelines, and 6.4% stated not being interested in these guidelines. Only 18.5% reported to know and use the EASD guidelines in their clinical practice.
Glucose-Lowering Treatment Patterns
Per the inclusion criteria, all patients had been treated with metformin, with or without other agents, prior to enrollment. On average, patients’ glucose-lowering medication had been changed 2.5 ± 1.6 times, and patients had been on 1.9 ± 0.8 different agents before treatment with vildagliptin was initiated. As shown in Table 2, most patients were started on vildagliptin in combination with metformin (92.9%), but some (7.1%) were started on vildagliptin only. At the time of enrollment, the most used concomitant glucose-lowering medications were glitazones and sulphonylurea (16.1 and 12.1%, respectively, of the patients). Among antihypertensive agents prescribed, 57.7% of patients were prescribed either an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor, whereas beta-blockers were prescribed in 31.0% of the patients. Consistent with the cardio-metabolic risk profile, 68.0% of patients were on statin therapy, while about one-half of patients (51.1%) were prescribed low-dose aspirin.
At visit 2, 22.7% of patients were switched to the SPC vildagliptin/metformin; a similar rate (22.1%) was observed at visit 3. As a result, the proportions of patients on the free regimen of vildagliptin and metformin therapy decreased to about two-thirds of patients at visit 2 (69.1%) and visit 3 (64.4%). The use of concomitant glucose-lowering medications remained constant with the exception of the class of glitazones: as a result of the initiation of vildagliptin, ± 13% of the patients were taken off glitazones, so the percentage of patients treated with glitazones decreased from 16.1% at baseline to 2.4 and 2.8% at visit 2 and 3, respectively.
When asked about their medication behavior in the preceding 4 weeks, the proportion of patients giving answers indicative of non-adherence decreased from baseline to visit 2 and 3 for all three adherence behaviors of interest, i.e. not having taken medication, skipping several doses and taking medication more than 2 h off schedule (all p < 0.01), as well as for the mean composite of frequency of non-adherence (p < 0.0001) (Table 2). Mean patient and physician VAS ratings of adherence increased by 3.1 and 5.3%, respectively, from baseline to visit 3 (p < 0.0001), and the VAS ratings of patient and physician were correlated highly at each of the three visits (all p < 0.0001). The most important reasons for patients’ poor adherence were forgetfulness of prescriptions (33.4%), lack of understanding of the importance of long-term continuing treatment (21.3%) and refusal to accept the chronic nature of the disease (14.0%). Suggestions given by the physicians to improve patient adherence were dosage simplification (31.5%) and provision of information to the patient (29.3%).
Effectiveness of vildagliptin was analyzed based on 1230 patients whose HbA1c levels could be obtained for all three time points of the study (at baseline and at visits 2 and 3). At initiation of vildagliptin therapy, the mean HbA1c was 8.2 ± 1.3%, and this value decreased significantly to 7.4 ± 1.0 and 7.2 ± 1.0% at 105 (visit 2) and 180 days (visit 3) (p < 0.0001), respectively. In addition, the proportion of patients who achieved the recommended glycemic target (HbA1c < 7%) increased from 8.6% at initiation of vildagliptin therapy to 35 and 44.6% at 105 and 180 days post-initiation of vildagliptin (all p < 0.0001), respectively (Fig. 2a, c). HbA1c goal attainment rates were highest among patients with baseline HbA1c of < 8.0% at initiation (Fig. 2e). In parallel, mean FPG levels decreased from 171.0 ± 53.3 mg/dL at baseline to 145.3 ± 44.4 and 141.1 ± 44.0 mg/dL at 105 and 180 days, respectively, whereas FPG goal achievement (FPG < 126 mg/dl) rate increased from 14.2% before initiation of vildagliptin therapy to 37.5 and 42.8% at days 105 and 180 post-initiation of vildagliptin (p < 0.0001), respectively (Fig. 2b, d).
As summarized in Table 3, mean BMI, total cholesterol, LDL-cholesterol, triglycerides, systolic blood pressure and ALT and AST values all decreased significantly from baseline to 180 days after initiation of vildagliptin, while no changes could be observed for HDL and diastolic blood pressure values. Importantly, waist circumference, a simple and valid marker for abdominal obesity, decreased significantly from baseline to day 180, both in male and female patients.
Patients who switched to the SPC of vildagliptin and metformin showed no difference in mean HbA1c at study end compared to those who remained on vildagliptin and metformin separately. However, the switched patients showed greater reductions in mean FPG (p < 0.01), and a higher proportion of these patients achieved the HbA1c (48.5 vs. 42.9%) (p < 0.01) and FPG (56.6 vs. 38.8%) (p < 0.001) goals despite similar patient-reported adherence rates. Compared to non-elderly patients, patients aged > 65 years evidenced HbA1c and FPG levels that were between 0.18 and 0.28% (p < 0.001), and between 3 and 6 mg/dL (p < 0.05), respectively lower. Moreover, compared to patients aged < 65 years, those aged ≥ 65 years had consistently higher HbA1c goal achievement rates at baseline (11.4 vs. 6.5%), 105 days post-initiation of vildagliptin (37.6 vs. 32.9%) and 180 days post-initiation of vildagliptin (47.8 vs. 41.8%; all p < 0.01), but not higher FPG goal achievement rates.
Thirty-seven patients (2.4%) reported a total of 56 AEs, mainly gastro-intestinal AEs (n = 24), whereas two cases of hypoglycemia were reported. Seventeen AEs were classified as SAEs, including three cases of death. Only one SAE, i.e. anorexia and weight loss, was suspected to be vildagliptin-related; this SAE was considered to be a sign of intolerance to vildagliptin, and treatment was stopped during hospitalization. AE/SAE rates and liver enzyme levels for elderly and non-elderly patients were statistically similar, as were AE/SAE rates for patients switched to the SPC vildagliptin/metformin.