An increased risk of some macrovascular conditions was observed in liraglutide initiators, compared with those initiating most other NIADs. However, after performing a stepwise adjustment, increased risk was only seen in liraglutide initiators compared with biguanide initators. These findings are likely explained by the differential drug choice applied to the different subpopulations of T2D. Compared with other NIAD initiators at baseline, liraglutide initiators had more advanced and longer duration of T2D, reflected by having more microvascular complications, more concomitant NIAD and insulin use and higher HbA1c levels. In addition, more components of the MetS were captured for liraglutide initiators. These findings suggest that UK physicians prescribed liraglutide to a selected T2D subpopulation who presented with MetS (selection bias) and/or had a more advanced stage of T2D, poorly controlled with the marketed antidiabetics available at the time liraglutide entered the market (chanelling bias).
The observed increase of macrovascular outcomes in the liraglutide initiator cohort may rather be due to the population’s baseline metabolic risk profile and not to liraglutide exposure itself (confounding). In addition, liraglutide initiators may have had other inherent residual baseline characteristics which have not been measured but increase CV risk (residual confounding), e.g. higher levels of hyperinsulinemia/insulin resistance (which are associated with MetS and independently associated with increased risk of CV outcomes [17]) or diabetic dyslipidemia (increased triglyceride levels, decreased high-density lipoprotein-cholesterol levels and increased small dense low-density lipoprotein particle levels), which is a component of the MetS and independently associated with increased risk of CV outcomes [2, 5, 18].
This study´s real-world findings on pre-liraglutide patient characteristics are in line with those reported by the UK Association of British Clinical Diabetologists’ audits, which examined data on 6238 liraglutide-treated patients from 2009 to 2013 [19]. Liraglutide users from diabetes centers across the UK were found to be heavier and with poorer glycemic control than patients from liraglutide phase 3 RCTs. The conclusion was that the baseline characteristics of liraglutide-treated patients were influenced by the UK NICE guidelines, which recommend liraglutide for patients with high BMI (≥ 35 kg/m2) [19]. Patients with higher BMIs inherently have a higher probability of having more cardiometabolic risk factors [12]. In addition, UK reimbursement conditions add to further confounding by indication, reinforcing that patients initiating liraglutide have higher CV risk [20].
In this study, liraglutide initiation itself appears to be an indicator for the presence of a higher clustering of cardiometabolic risk and more advanced disease stage within the continuum of T2D. The same appears to apply to exenatide, which can be expected, as both belong to the same drug class (GLP-1RAs).
Non-interventional database studies lack randomization, with resulting bias and confounding. This is a specific problem in T2D, where increasing diabetes severity (comorbidities/complications and stage of progression) is followed by treatment steps, and lack of response leads to treatment intensification. Thus, separating disease severity from treatment exposure as the causal agent for increased incidences of CV outcomes in a heterogeneous T2D population, as in the presented study, can be challenging. Baseline treatment characteristics must be balanced between cohorts to achieve homogeneity across cohorts. In order to finalize a study design with homogeneity across treatment cohorts, thorough background knowledge is required, encompassing the disease and its natural history, complications and comorbidities, the likely real-world target population of the drug and current local pharmacotherapy guidelines, and the feasibility of obtaining required data from the chosen source.
The presented study highlights that comparative analysis of treatment initiator cohorts, without thoroughly balancing baseline characteristics, is not suited to addressing new drug safety. In this study, patient baseline characteristics had not been matched among cohorts. In addition, it was not possible to adjust for all of the a priori planned covariates, owing in part to the rarity of the outcomes under investigation. Risk estimates for liraglutide initiators are likely to have been increased when adjusting for age, since liraglutide users were younger. Even with a relatively large database such as the CPRD, the comparison of a new drug to existing therapies was challenging due to the heterogeneity of the populations treated with different drugs, and the relatively low numbers of new drug initiators.
Of note, real-world liraglutide observational data emerging from comparative studies based on cohorts which had been matched (baseline characteristics were equally weighted across cohorts) have shown that liraglutide use was associated with significantly lower major adverse CV event (MACE) risk [21]. Additionally, CV outcomes trials with GLP-1RAs have not reported increased CV risk [13]. The blinded, randomized, placebo-controlled LEADER trial demonstrated that MACE risk was signficantly reduced in liraglutide- versus placebo-treated patients [22]. These findings support our interpretation that selection bias, confounding and possibly channelling bias drive the observed increased CV risk in liraglutide initiators in the UK real-world setting in the presented study.
Observational studies provide external validity of a drug’s safety and effectiveness in everyday clinical practice, thus supporting decision-makers and key stakeholders regarding treatment options to be carried out in the real world [23]. Observational PASS are key in gathering this type of real-world evidence. However, as patients are not randomized, the study design for investigating the safety of newly marketed products should, to the extent possible, account for confounding and bias. This requires the feasibility of aquiring sufficient data quantity and quality to obtain true homogeneity among cohorts. These considerations are in line with the Guidelines for Good Pharmacoepidemiology Practice [24] and should be taken into account also when designing and interpreting studies that seek to support regulatory decisions.
This regulatory health authorityrequired PASS sought to investigate the safety of liraglutide in the UK realworld setting. CPRD GOLD reflects the UK real-world clinical practice setting [16]. Patients prescribed liraglutide had higher components of the MetS and markedly more advanced T2D than NIAD initiators. It was not always possible to adjust for all confounders and, in some cases, this may have modulated safety outcomes, although in others, significant results persisted despite adjustment for all confounders (e.g. comparison with biguanides). The study design allows for a descriptive analysis of the cohort populations initiating different antidiabetic medications. An improved study design to assess CV safety with liraglutide would require equally weighting the baseline characteristics. This study was endorsed by the health regulatory authorities at a time before the establishment of the Pharmacovigilance Risk Assessment Committee (PRAC). PRAC is responsible for reviewing the design and for the evaluation of post-authorisation safety studies. In addition, this observational real world study was thought to complement the the liraglutide Cardiovascular Outcome Trial (CVOT), LEADER, which was also a regulatory authority required PASS at the time of marketing authorization (2009).