A total of 33,010 physicians were contacted, of whom 1032 agreed to participate in the study. Of these, 814 (78.9%) responded before the quota of participating physicians had been reached; of these, 667 (81.9%) completed the administrative procedure and participated in the study and 304 (45.6%) recruited at least one patient into the ambispective cohort. Of the 304 “active” physicians, 80.6% were GPs, and 19.4% were specialists (Table 1). Their mean (±SD) age was 52 ± 8 years, and 76% were male. A majority of participating general practitioners were in private practice (93.8%); in contrast, 33.9% of endocrinologists/diabetologists were in private practice, 41.1% practiced in the public sector, and 25.0% had a mixed practice. Almost all of the participating physicians (93.5%) had at least one patient who was receiving saxagliptin prior to their participation in the study. Compared with the participating physicians, non-participating physicians (those who refused to participate or did not return financial agreements before inclusion) were more likely to be female (23% versus 43%, respectively), work in the public sector (7.5% versus 18.4%) and have no patients receiving saxagliptin (6.5% versus 40.9%).
The demographic characteristics of the 304 active physicians are summarized in Table 1 and compared with those of a geographically representative sample of French physicians drawn from the DREES database . The two populations were generally comparable, except for a higher percentage of males and a much higher percentage of general practitioners in private practice among the participating physicians.
Data collection for the ambispective cohort took place from 22 June 2012, and the mean duration of follow-up was 20.9 months [95% confidence interval (CI) 20.4–21.4]; 73.6% of participants were followed for 24 months. A total of 24 physicians discontinued their participation during the study, resulting in 56 people with type 2 diabetes being lost to follow-up.
A total of 1131 participants were enrolled into the ambispective cohort, of whom 98 (8.7%) were subsequently excluded; the most common reason for exclusion (n = 81, 82.7%) was no treatment with saxagliptin started at enrollment or in the 6 months prior to enrollment. Thus, the analysis of the ambispective cohort included 1033 participants, of whom 97.5% were treated with saxagliptin and the remainder with a saxagliptin/metformin fixed-dose combination. Overall, 777 participants (75.2%) were enrolled by GPs; the mean number of patients enrolled by each active physician was 3.6 (range 1–8).
The clinical characteristics of participants in the ambispective cohort at the time of starting saxagliptin are summarized in Table 2. The mean age of the patients at the time of diagnosis of type 2 diabetes was 54.3 years (95% CI 53.6–55.1), and the mean age at starting saxagliptin was 61.2 years (95% CI 60.4–61.9). The mean BMI at baseline was 29.8 kg/m2 (95% CI 29.5–30.2), and 83.9% of patients were overweight (BMI ≥25 kg/m2). The mean HbA1c level at baseline was 8.0% (95% CI 7.9–8.1%), and 79% of patients had an HbA1c level ≥7%.
Overall, 26.9% of the participants had at least one microvascular diabetic complication, and these were more likely to be enrolled by specialists than by GPs. For macrovascular complications, 4.2% had angina pectoris, 5.1% a history of myocardial infarction, 2.5% a stroke and 1.6% heart failure. Treatment for dyslipidemia was prescribed for 62% of the population, and a similar percentage was prescribed antihypertensive therapy. Secondary cardiovascular prevention status was observed in 13% of the patients, i.e., those patients presenting with angina, myocardial infarction, peripheral arterial disease or stroke when starting saxagliptin.
Patient selection biases were assessed by comparing data from included and non-included patients. Compared with non-included patients, included patients weighed slightly less (P = 0.041), had a lower BMI (P = 0.014), were younger at time of T2D diagnosis (P = 0.015), had been diagnosed with T2D for a longer period of time (P < 0.0001) and the last known HbA1c value before consultation was slightly lower (P < 0.0001).
Prior to starting saxagliptin, the majority of participants (91.3%) were prescribed oral glucose-lowering drugs alone, with 6.0% prescribed either insulin or a GLP-1 analog alone or with oral drugs, and 2.8% were not receiving any glucose-lowering medication. Compared with GPs, specialists were slightly less likely to prescribe oral drugs alone and more likely to prescribe insulin. Among the participants receiving oral drugs alone, 66.4% were on monotherapy, 28.9% on dual therapy and 4.7% on combinations of three or more agents. Specialists were more likely than GPs to prescribe dual combination therapy: 35.1% of participants enrolled by specialists were receiving dual combination therapy compared with 27.0% of those enrolled by GPs. Metformin was the most commonly used oral glucose-lowering drug, accounting for 83.8% of people receiving monotherapy. The most widely used combination was metformin with a sulfonylurea, which was prescribed for 66.1% of people prescribed dual combination therapy. The mean doses of metformin in people on monotherapy and on dual combination therapy were 2032 mg/day (95% CI 1977–2087) and 2164 mg/day (95% CI 2087–2241 mg), respectively.
Starting Saxagliptin Therapy
For the majority of participants (97.4%), saxagliptin was started by the participating physician, and for 61.2%, saxagliptin was started at the time of enrollment into the study. The most commonly prescribed regimen (52.9%) was a combination of saxagliptin and metformin; 15.1% were prescribed saxagliptin monotherapy, 15.6% a combination of saxagliptin, metformin and a sulfonylurea, and 6.1% a combination of saxagliptin with a sulfonylurea. Combination therapy with saxagliptin and metformin accounted for 55.3% of prescriptions by GPs and 45.9% of prescriptions by specialists. The most common reason for starting saxagliptin was inadequate glycemic control, in 81% of the patient, followed by intolerance to the previous glucose-lowering therapy.
In total, 582 saxagliptin prescriptions (56.4%) were in compliance with the therapeutic indications for saxagliptin and saxagliptin/metformin fixed-dose combination applicable at the time the data were analyzed [22, 23]. The most common cause of non-compliance, accounting for 57.4% of non-compliant prescriptions, was the use of glucose-lowering medications prior to starting saxagliptin that were not specified in the therapeutic indications. Treatment with metformin alone should have been prescribed before starting saxagliptin; however, 6.3% of participants did not receive any treatment, 14.7% switched to saxagliptin from another DPP-4 inhibitor, and 36.4% received another treatment not specified in the therapeutic indications. In 22.6% of participants, HbA1c values were outside the range specified in the French Guidance for Diabetic Treatment ; in 16.7%, a saxagliptin-containing combination prescribed at starting saxagliptin was not indicated, and in 10.3% of cases, when saxagliptin was started in participants who had previously received metformin alone, it was not due to intolerance to metformin.
According to the definition used by the French authority CNAMTS , 92.7% of saxagliptin prescriptions at baseline conformed to the therapeutic indications, and 76.7% met the conditions for reimbursement. Overall, 76.7% were in compliance with both the therapeutic indications and the conditions for reimbursement.
Retention of Saxagliptin Therapy
The overall saxagliptin retention rate at 2 years, estimated by the Kaplan-Meier method, was 78.6% (95% CI 76.0–81.3). The retention rate was higher among participants enrolled by GPs than among those enrolled by specialists (83.6% versus 58.3%, respectively). Similar trends were seen at 6, 12 and 18 months (Fig. 1).
The most common reasons for discontinuation among the 112 patients who discontinued saxagliptin during the 2-year follow-up period were inadequate glycemic control (52.1%) followed by intolerance (21.8%), patient request (14.2%) and poor adherence to therapy (7.8%). Overall, the proportion of participants discontinuing treatment was three times higher among patients enrolled by specialists compared with those enrolled by GPs (21.2% versus 7.4%, respectively); participants enrolled by specialists were more likely to discontinue treatment because of poor tolerability (25.8% versus 18.1%), but less likely to discontinue because of poor adherence (4.2% versus 11.1%). The most common therapies prescribed following discontinuation of saxagliptin were metformin monotherapy (18.3%), metformin plus a sulfonylurea (14.2%), insulin (12.9%) and insulin plus metformin (5.7%).
HbA1c and Weight Under Saxagliptin Therapy
The mean HbA1c at 2 years was 7.0%, with 49% having an HbA1c <7%, increased from 21% prior to starting saxagliptin (Fig. 2). When tested individually, the factors retained to estimate the HbA1c value over time were glucose-lowering treatment prescribed and regular physical exercise. These factors were subsequently confirmed in the final multivariable model with P < 0.0001 and P = 0.0008, respectively. Time from diagnosis to saxagliptin initiation, age at saxagliptin initiation, physician specialty and time were also found to significantly influence the HbA1c value over time (P < 0.0001 for all effects). The mean HbA1c level estimated by the multivariable analyses decreased from 8.1% (95% CI 7.9–8.2) at baseline to 7.1% (95% CI 7.0–7.3) at 2 years (Fig. 2). There was little difference between observed HbA1c levels over time and HbA1c values estimated by the multivariable analyses.
At 2 years, participants treated with saxagliptin showed a mean weight change of −2.0 kg (95% CI −2.4 to −1.7). No factors individually tested were statistically significant. Age at saxagliptin initiation (P = 0.0222), weight at baseline (P < 0.0001) and time from diagnosis to saxagliptin initiation (P < 0.0001) were found to significantly influence change in weight in the final model. Mean weight change at 2 years estimated by the multivariable analysis was −1.8 kg (95% CI −2.2 to −1.5).
Hypoglycemic Episodes, Adverse Events and Comorbidities Under Saxagliptin Therapy
A total of 294 hypoglycemic episodes were reported in 70 participants (6.8%) during the follow-up period. Of these, 143 episodes in 41 people (4.0%) occurred while saxagliptin was prescribed in combination with agents associated with hypoglycemia, such as insulin, sulfonylureas or glinides. Seven severe hypoglycemic events occurred in six people (0.6%), of whom one was prescribed saxagliptin with a sulfonylurea and one was prescribed saxagliptin plus insulin.
During the follow-up period, adverse events were reported in 228 participants (22.1%), of whom 23 (2.2%) experienced adverse events that were considered to be saxagliptin-related (Table 3). Serious adverse events occurred in 84 participants (8.1%), of which 6 events in 2 participants were considered to be saxagliptin-related: one woman had increases in lipases and transaminases, and one man reported loss of consciousness, speech disorder, hyperhidrosis and staring.
New comorbidities were reported in 102 participants (11.7%); the majority (n = 80) developed renal disorders and 25 cardiovascular disease. Among the patients who developed renal disorders, 62 (79.5%) had at least one episode of microalbuminuria, 6 (7.8%) presented with renal impairment (creatinine clearance <60 ml/min), and 13 (19.4%) presented with proteinuria. New cardiovascular diseases were not considered to be associated with saxagliptin treatment; seven people developed a stable angina pectoris, five a myocardial infarction, five a stroke, five peripheral arterial occlusive disease of the lower limbs and three heart failure.