Effectiveness and Persistence with Liraglutide Among Patients with Type 2 Diabetes in Routine Clinical Practice—EVIDENCE: A Prospective, 2-Year Follow-Up, Observational, Post-Marketing Study

Randomized controlled trials (RCTs) represent the reference standard in terms of assessing the efficacy and safety of any therapeutic agent, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as liraglutide, which are considered in the American Diabetes Association/European Association for the Study of Diabetes 2015 position statement [1]. The results of the Liraglutide Effect and Action in Diabetes (LEAD) program demonstrated the anti-hyperglycemic efficacy of liraglutide as monotherapy and combined with other agents in the treatment of patients with type 2 diabetes (T2D) in RCTs. Furthermore, the LEAD program highlighted the low risk of hypoglycemia associated with liraglutide and the additional benefit of clinically relevant weight loss and decreased systolic blood pressure [2‐8].

Observational studies are important to explore how treatments, such as liraglutide, are used in a real-life setting. Real-life data provide crucial information to evaluate the effectiveness of therapeutics in clinical practice and are being requested more and more frequently by health authorities. The Association of British Clinical Diabetologists (ABCD) conducted a nationwide audit in the UK to assess the safety and effectiveness of liraglutide in real-life clinical practice. Data from this audit demonstrated that, after 6 months of treatment, liraglutide 1.2 mg was effective in terms of reducing HbA_1c (more so in individuals with a higher baseline HbA_1c) and well tolerated [9, 10]. Furthermore, data from the IMS Health integrated claims database in the USA demonstrate that, in clinical practice, liraglutide (once daily) has greater effectiveness [in terms of HbA_1c reduction and improved glycemic goal attainment (HbA_1c <7.0%)] compared with either exenatide (GLP-1RA, twice daily) or sitagliptin [dipeptidyl peptidase-4 (DPP-4) inhibitor, once daily] in patients with T2D [11].

Following liraglutide’s approval in France by the European Medicines Agency (EMA) in July 2009, the French Health Authority (FHA) requested the current study with 2 years of follow-up to evaluate conditions for prescription, maintenance dose, effectiveness, and safety of this therapy in routine clinical practice.

The EVIDENCE study was a prospective, observational study that aimed to assess conditions for prescription, maintenance dose, effectiveness, and safety of liraglutide in routine clinical practice in France. To minimize the limitations associated with the design of an observational study, physicians were chosen at random from a large sample and the number of patients recruited by each physician was limited to prevent a cluster effect. In total, 992 physicians at 992 sites in mainland France participated in the study. Therefore, this study can be considered representative of the national profile. Throughout the study, all contact between the sites and the sponsor went through the research organization to avoid bias in the delivery of routine care, and quality control was applied to each step of data handling, ensuring the correctness of all data, specifically regarding safety reporting. As this was an observational study, with no control group, the results are indicative of certain combinations and cannot give rise to cause-and-effect relationships. Furthermore, the complete data are not available for analysis for all patients, as any missing data were not replaced.

In the EVIDENCE study, the main motivation for physicians to prescribe liraglutide was to improve glycemic control. The studies in the LEAD program have shown that liraglutide may provide greater benefit when used earlier in the course of disease progression [2, 4]. In the EVIDENCE study, only ~20.0% of patients were receiving OAD monotherapy at the time of initiation of liraglutide. Additionally, compared with patients in the LEAD studies, patients included in the EVIDENCE study were slightly older (mean age 58.7 vs. ~52.0 to ~58.0 years) and more obese (70.8% of patients had a BMI ≥30 kg/m² in the EVIDENCE study vs. 59.6% of patients across the six LEAD studies) [2‐8, 14]. Taken together, this may suggest that liraglutide was initiated later in the disease course in the EVIDENCE study than in the LEAD studies. Indeed, the mean duration of diabetes for patients was 9.7 years in the EVIDENCE study and between 6.5 and 9.4 years in the LEAD studies [2‐8]. One possible explanation for this is related to the guidelines available during the course of the EVIDENCE study that recommended the use of GLP-1RAs as second-line therapy [15]. Furthermore, 15.6% of patients were treated with insulin prior to liraglutide introduction in the EVIDENCE study, while this was not permitted in the LEAD studies [2‐8], thus confirming that the EVIDENCE study included a different patient population compared with the LEAD studies. It is of note, however, that patients included in the EVIDENCE study had similarly poorly controlled diabetes (mean HbA_1c 8.5%) to those in the LEAD studies (mean HbA_1c 8.1–8.6%) [2‐8].

Mean HbA_1c reduction, amounting to −1.0%, at the end of the EVIDENCE study, was clinically relevant and compared well with that in the LEAD RCTs (−0.8% to −1.5%) [2‐8] and other real-world studies (−0.9% to −1.6%) [16‐18]. Furthermore, liraglutide was associated with optimal glycemic control (HbA_1c <7.0%) in ~30.0% of patients after 2 years of treatment, while only 9.8% of patients had HbA_1c <7.0% at baseline. The proportion of patients achieving optimal glycemic control in the EVIDENCE study is almost identical to results from a recent 26-week UK-based real-world study (29.3%) [16] and only slightly below the ~35.0% to ~45.0% reported after 26 weeks of treatment in the LEAD RCTs, which shows liraglutide’s effectiveness under standard conditions for use [2‐5, 7, 8]. When comparing data from the EVIDENCE study with that from the LEAD-3 extension study (18 months in duration), a greater difference in patients achieving optimal glycemic control (HbA_1c <7.0%) is apparent, i.e., ~30.0% in EVIDENCE vs. ~53.0–58.0% in the LEAD-3 extension study [19]. However, it is possible that the proportion of patients achieving optimal glycemic control in the LEAD-3 extension study is influenced by survivor bias.

Real-world data demonstrate that most T2D patients starting GLP-1RA therapy have a high BMI [20], and previous studies have shown that liraglutide is associated with weight loss [21, 22]. Moreover, a recent study showed that, across the LEAD studies, higher initial BMI was associated with slightly greater weight loss with liraglutide [14]. Therefore, unsurprisingly, the desire for improved weight control was an important motivation for physicians to prescribe liraglutide in the EVIDENCE study. In total, 95.2% of patients involved in the EVIDENCE study had a baseline BMI ≥25 kg/m² and, as reported in RCTs [2‐8] and other real-world studies with liraglutide [16‐18], the reductions in both weight and BMI seen throughout the EVIDENCE study were statistically significant. Although the impact of such weight loss in T2D remains to be demonstrated in terms of prognosis, this trend may be enough to at least improve patient quality of life.

Throughout the study, the most commonly prescribed oral antidiabetic treatments remained stable with the introduction of liraglutide. However, there was a reduction in the use of DPP-4 inhibitors from 40.1% to 9.7%. This may be expected, as data from an open-label extension study demonstrate the switch from DPP-4 inhibitor to liraglutide to be beneficial, both in terms of glycemic and weight control [23]. Moreover, liraglutide is not indicated for use in combination with DPP-4 inhibitors [12], and combinations of incretin-based therapies are not well studied to date and the theoretical benefits appear to be relatively limited [24]. Finally, it is not currently known whether there may be an increased risk of AEs when GLP-1RAs and DPP-4 inhibitors are used in combination. At the end of study, 191 patients were still being treated by a combination of liraglutide and a DPP-4 inhibitor. This may be interpreted as a lack of interaction between the sponsor and the physicians. Throughout the study, there was a reduction in the prescription of glitazones from 14.1% to 3.0%. This observation may have been largely due to the withdrawal of these drugs from the French market during the study period and physicians’ concerns regarding patients’ weight.

Patients initiating liraglutide treatment should be transferred from the starting dose of 0.6 to 1.2 mg/day after at least 1 week [12]. This dose can then be increased further to 1.8 mg/day for patients who require increased glycemic control. Consequently, at the end of study, about half of the study population were on the 1.2 mg/day dose and half were on the 1.8 mg/day dose. At the 12-month timepoint, 36.2% of patients were on the 1.8 mg/day dose and about 58.0% were on 1.2 mg/day. This finding compares well with results from a recent real-world study (32.7% and 64.6%, respectively) [17].

Throughout the study, even though the use of SUs and glinides remained stable and the use of insulin increased, the percentage of patients suffering at least one hypoglycemic episode (during the 4 weeks of preceding visits) decreased from 6.9% (baseline measure) to 4.4% and only nine patients experienced a severe hypoglycemic episode during the entire 2 years of follow-up. To put this into perspective, 11 patients experienced a severe hypoglycemic episode during the 4 weeks preceding inclusion in the study. All patients who experienced a severe hypoglycemic episode were also being treated with both biguanides and SUs or with insulin and glinides. Therefore, it is likely that liraglutide was not the cause of the severe hypoglycemic episodes, and data from the LEAD-3 trial demonstrated no cases of severe hypoglycemia when liraglutide was used as monotherapy [6]. However, with the lack of a control arm in the EVIDENCE study, it is difficult to conclusively evaluate this.

The most frequently reported AE type in this study was classified as belonging to gastrointestinal (GI) disorders, and the frequency reported (10.9%) was similar to that reported in another real-world study (11.4%) [17]. However, this occurrence is considerably lower than that observed with liraglutide in the LEAD RCTs (~33.0% to ~56.0%) [2‐8]. This may be due to the less controlled nature of safety reporting in this observational study which is a well-known phenomenon in non-RCTs [25]. However, it may also be possible that a prolonged dose escalation period in the EVIDENCE study may have contributed to this observation.

Based only on very limited data [26‐30], some researchers have suggested that therapy with GLP-1RAs may increase the risk of pancreatitis [31, 32]. During this study, there were four cases (0.1%) of acute pancreatitis, which is in agreement with the current SmPC for liraglutide (<0.2%) [12]. The incidence of acute pancreatitis in this study was 0.8 cases per 1000 patient-years, which compares well with a rate of 1.6 cases per 1000 patient-years reported in a recent meta-analysis of 18 clinical trials involving liraglutide [33], and is less than the background incidence (4.2 cases per 1000 patient-years) in people with T2D [34]. This finding also relates well to another recent study, which suggests that the use of incretin-based drugs appears not to be associated with an increased risk of acute pancreatitis [35]. However, vigilance still needs to be conducted, as a recently published analysis suggests that, compared with other anti-hyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France [36]. At present, neither the US Food and Drug Administration (FDA) nor the EMA have reached a final conclusion regarding a causal relationship between GLP-1RAs and pancreatitis or pancreatic cancer. However, both agencies do agree that assertions concerning a causal association between incretin-based drugs and pancreatic safety, as expressed recently in the scientific literature and in the media, are inconsistent with the current data [37]. Overall, the safety profile for this study is in accordance with what is reported in the SmPC for liraglutide [12] and does not, therefore, alter liraglutide’s risk–benefit profile.

Finally, results from the EVIDENCE study show an increase in patients’ treatment satisfaction after initiating liraglutide therapy in a real-world setting, and treatment satisfaction has been shown to be associated with increased adherence to treatment [38] and lower HbA_1c values [39, 40].

The results of the EVIDENCE study suggest that the effectiveness of liraglutide in real-world clinical practice is similar to that observed in RCTs, even though there were important demographic and clinical differences between the patient populations. In addition, the incidence of GI events was considerably lower in EVIDENCE than in RCTs. Overall, the results from this observational study suggest that treatment with liraglutide translates into therapeutic benefits for patients with T2D in routine clinical practice.