Abstract
Introduction
Glucagon-like peptide 1 receptor agonists (GLP1RAs) are licensed for the treatment of type 2 diabetes (T2D). They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in terms of glycaemia, and in some cases, reducing CV events) in extensive randomised controlled trials (RCTs). However, there remain concerns regarding the generalisability of these findings (to those ineligible for RCT participation) and about non-CV safety. For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of RCTs findings to broader populations and explore safety, for which RCTs are not usually powered, in more detail.
Method
We did a pre-planned and registered (PROSPERO registration CRD42020165720) systematic review of population-based studies investigating GLP1RA effectiveness and safety, following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines.
Results
A total of 22 studies were identified (including 200,148 participants and 396,457 person-years of follow-up) exploring exposure to GLP1RA class, exenatide and liraglutide (the only individual drugs with treatment effect estimates identified) on mortality, cardiovascular disease (CVD), acute pancreatitis (AP), pancreatic cancer (PC), thyroid cancer (TC), acute renal failure (ARF), diabetic retinopathy (DR), breast cancer (BC) and hypoglycaemia. For CV and mortality outcomes, studies confirmed the associated safety of these drugs. For liraglutide, point estimate (PE) range (PER) major adverse cardiovascular events (MACE) (0.53–0.95) and PER heart failure (0.34–1.22) were similar in direction to the beneficial effect observed in RCTs for MACE but varied widely for heart failure. For safety outcomes, exposure was not associated with AP (PER 0.50–1.17), PC (PER 0.40–1.54), BC (PER 0.90–1.51) or hypoglycaemia (PER 0.59–1.06). Only one study was identified exploring each of TC (no evidence of association, hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.98–2.19), renal outcomes (no evidence of association, HR 0.77, 95% CI 0.42–1.41) and DR (no evidence of association, HR 0.67, 95% CI 0.51–0.90).
Conclusion
In T2D, GLP1RAs appear safe from the CV perspective and (for liraglutide) may have associated benefit in primary as well as secondary CVD prevention. For non-CV safety, GLP1RA exposure was not associated with an increased risk of AP, PC, BC or hypoglycaemia; the other outcomes had too few studies to draw firm conclusions and should be explored further.
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Glucagon-like peptide 1 receptor agonist (GLP1RA) are licensed for the treatment of type 2 diabetes (T2D). |
For cardiovascular effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of randomised controlled trials (RCTs) to broader populations not eligible for trial participation and explore safety, for which RCTs are not usually powered, in more detail. |
We did a pre-planned and registered, agnostic systematic review asking: do the benefits of GLP1Ras in T2D extend to those ineligible for RCT participation, and are safety concerns which arose during the trials (or in post-marketing) detected, in population-based observational pharmacoepidemiology studies? |
We considered and reported all clinical event-based outcomes for effectiveness and safety in studies which met our inclusion/exclusion criteria. |
For cardiovascular (CV) and mortality outcomes, studies confirmed the associated safety of these drugs and, for liraglutide, correlated closely with the findings from RCTs, which may extend to primary CV disease prevention. |
For safety outcomes, GLP1RA exposure was not associated with an increased risk acute pancreatitis, pancreatic cancer, breast cancer or hypoglycaemia. There were insufficient studies to draw conclusions with regards to thyroid cancer, renal outcomes and diabetic retinopathy. |
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Introduction
Glucagon-like peptide 1 receptor agonists (GLP1RAs) are licensed for the treatment of type 2 diabetes (T2D). GLP1RAs have been shown to improve glycaemic control via regulation and restoration of incretin function, leading to enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon secretion and food intake [1].
The clinical development programmes for these agents have robustly assessed the efficacy and preliminary non-cardiovascular (CV) safety of GLP1RA drugs for use in people with T2D. Several have subsequently been assessed for CV safety in large outcome trials, which have yielded mixed results in terms of effect on cardiovascular disease (CVD; liraglutide, subcutaneously administered semaglutide and dulaglutide all reduce CVD, lixisenatide, extended release exenatide and orally administered semaglutide do not) although all appear to be safe from the CV perspective [2,3,4,5,6,7,8]. Nevertheless, it remains unclear whether the CV benefit (if any) of these medicines extends to people who were not eligible to participate in randomised controlled trials (RCTs).
Population-based database studies present more generalisable data which can help broaden and expand the findings of RCTs. Although many population-based studies apply appropriate study design and statistical methods for control of confounding, these studies are at higher risk of confounding and bias than RCTs because they are not randomised or blinded. For CV effectiveness and safety, they can confirm and extend the finding of RCTs to more heterogeneous populations, especially those ineligible for trial participation. RCTs are not powered to detect adverse events, thus it often remains unclear whether safety signals identified in trials are a true effect or due to chance. As such, for non-CV safety, large, observational studies remain an important tool to identify the risk of harm, and if detected, to identify characteristics of participants that are associated with risk.
Here we describe the conduct and findings of a systematic review of population-based, database effectiveness and safety studies of GLP1RAs in T2D, either as a class or as individual agents.
Methods
We prospectively registered an impartial systematic review of population-based, observational studies examining effectiveness and safety of GLP1-RA agents in T2D (PROSPERO registration CRD42020165720, 16 January 2020). We hypothesised that these studies, if properly conducted, would show similar estimates for effectiveness and safety to those described in previous literature (Table 1).
We followed Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines for reporting the systematic review. In brief, we employed two search methodologies (maximal and targeted search) and interrogated the following research databases: Web of Science, Medline, EMBASE and EMCARE on Ovid, and CINAHL on EBSCO using the search criteria listed in the supplementary material (Table S1). We searched for studies published between 28 November 2006 (date of licensing of exenatide) and end of January 2020. We eliminated duplicates using each study’s unique identifier. Two reviewers (JT and TC; TC, medically qualified) independently applied the inclusion and exclusion criteria first to the title and then to the abstracts of potentially eligible studies (Table S2). We searched ENCePP, ClinicalTrials.gov and the EU clinical trials register as well as the references of eligible studies to identify further publications which may not have been identified in our searches. We only included English language studies because of resource limitations.
Each reviewer checked 10% of the other’s title and abstract screening. If there was less than 95% agreement we pre-specified that the entire list would be re-screened. Third party arbitration of disputes was planned in the event of less than 95% agreement. There was 100% agreement on the 10% of included/excluded studies so this step was not necessary.
The studies eligible for inclusion were scored for quality (using the Downs and Black Checklist for Non-Randomised Studies) [9] but we did not employ a quality score cut-off for inclusion/exclusion (Table S3). The quality score has been shown to have good inter-rater reliability [10].
We then extracted study information from the studies identified using a standardised data extraction template (Table S4). We included all reported clinical event outcomes but decided post hoc not to include the reporting of surrogate markers (continuous variables, e.g. glycated haemoglobin (HbA1c)).
All clinical event outcomes were included.
We tabulated the study information, point estimates and confidence intervals (CIs) (including relevant subgroup information) by outcome, so studies may appear in multiple tables (Tables S5, S7, S8, S9, S10, S11, S12, S13). For safety outcomes, where there were more than three studies exploring an outcome, we made forest plots for visual comparison.
We chose to describe studies with fewer than 5000 participants as small; 5000–20,000 participants as medium-sized; more than 20,000 as large. CI widths are described qualitatively.
We did not apply meta-analytic methods to the identified studies because of axiomatic breaches in principles of meta-analysis (too few studies exploring a particular outcome, significant diversity in study design, confounder adjustment and analysis methods, multiple effectiveness estimates derived from same data source giving rise to possible double counting, and studies examining different GLP1RA agents; these breaches either rendered the effectiveness estimates uncombinable or would lead to a false illusion of precision) [11]. In addition there were too few studies for each outcome to provide funnel plots to assess the risk of publication bias (Cochrane Library recommends more than 10 studies) [12]. Thus we present a narrative systematic review.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Results
Figure 1 shows a flow diagram of the studies included at each stage of applying our inclusion and exclusion criteria. The search results and the reviewers’ inclusion and exclusion decisions are available on request. We present a synopsis of each study by outcome in Tables 2, 3, 4, 5, 6, 7, 8 and 9. Further information on the included studies are presented in Tables S5, S7, S8, S9, S10, S11, S12 and S13.
PRISMA diagram
We found 22 studies in total of which 12 were commercially funded [13,14,15,16,17,18,19,20,21,22,23,24,25] and 10 were funded by academic/non-profit/government organisations [26,27,28,29,30,31,32,33,34,35]. Six studies were identified through reference searching. The total number of participants in the studies was 200,148 with follow-up of 396,457 person years (PYs).
Table S3 reports the quality score agreed by two independent reviewers (TC and JT). The scores ranged from 12 to 22 (the maximum achievable score would have been 29/31 as none of the studies was randomised). None of the study designs as described appeared to have been affected by immortal time bias arising from an inappropriate start date to follow-up.
The only individual agents investigated were exenatide or liraglutide, other agents were included in GLP1RA class studies but without information being provided on individual agent effectiveness or safety estimates.
Cardiovascular Disease
GLP1RA class: three studies explored the effect of the GLP1RA class overall on CVD with two finding no association and one finding an associated reduction in major adverse cardiovascular event (MACE) [26, 32, 34]. Specifically, when compared to other antihyperglycaemic agent (AHAs, including injectable therapies) head-to-head, one study (where the class comprised 72% exenatide, 29% liraglutide; 9–13% had established CVD, and 100% were on background metformin) showed no association for MACE (and its components; Tables 2.1, S5.4, S6), irrespective of baseline HbA1c and consistent in subgroup analysis [32]. Versus oral antidiabetic drug (OADs, excluding injectable therapies) (in those already exposed to insulin and overweight; exenatide 72%, liraglutide 28%, 100% background insulin, 20% baseline CVD; Tables 2.2 and S5.5), another study showed an associated reduction in MACE (driven by a mortality reduction). In the same study, for a composite of non-fatal MACE components and for hospitalised heart failure (HHF) (primary CVD prevention only) there was no association [26]. Another study of a population at low risk of CVD suggested that GLP1RA exposure was associated with no effect on incident CVD compared to people not exposed (Tables 2.3 and S5.7) [34].
Exenatide: we found four studies that reported a CVD-related outcome for exenatide alone. Three reported a reduction in CVD associated with exenatide, and one reported no association [3, 13, 33, 35].
Compared to OADs: one study showed an associated reduction with exenatide exposure for a myocardial infarction (MI), stroke and coronary revascularisation composite and also CVD-related hospitalisation (where lipid levels, obesity and prior CVD rates were higher in the exenatide-exposed; Tables 2.4 and S5.1) [13]. Another showed no association in all-cause hospitalisation, but featured insufficient cases to allow for assessment on HHF (Tables 2.6 and S5.3) [3, 35].
Compared to insulin (which is known to increase the risk of CVD [36]), exenatide exposure was associated with a reduction in HHF, stroke and an MI/stroke composite but not MI alone (Tables 2.5 and S5.2); there was an associated reduction in all outcomes when those without pre-existing CVD or CVD/chronic kidney disease (CKD) were analysed separately [33]. Those with higher baseline HbA1c had a greater associated reduction in HHF alone and MI/stroke composite. A final study for exenatide showed no association towards reduction in MACE. For primary CVD prevention only, there was no association for the non-fatal CVD composite, MI, HHF and stroke (independent of baseline HbA1c; data not shown (DNS)) (Tables 2.2 and S5.5) [26].
Liraglutide: two studies reported the effect of liraglutide on CVD [23, 26]. Both showed reductions in MACE in the population overall (driven by a mortality reduction), in populations with less established CVD – 20% [26] and 16% [23] vs. 81% in Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) [6] and similar levels of baseline glycaemic control [23, 26]. Against dipeptidyl peptidase 4 inhibitors (DPP4i), one study showed a reduction in MACE overall and in secondary, but not primary, CVD prevention (Tables 2.7 and S5.6). Women, those aged 65 years or more, and those on baseline insulin benefitted most from this associated reduction in subgroup analysis (DNS) [23]. Versus insulin, the other study showed an associated reduction in MACE but no association for MI, stroke, MI/stroke composite and for HHF, independent of baseline HbA1c (Tables 2.2 and S5.5; MI/stroke/HHF explored primary prevention only, DNS) [26].
Mortality
For GLP1RA class overall (vs. unexposed, i.e. usual care) exposure was associated with an all-cause mortality (ACM) reduction irrespective of baseline body mass index (BMI), CVD status and BP (Tables 3.1 and S7.1) but a greater associated benefit in those with more diabetes mellitus (DM) complications and in older people (DNS) [34]. Against insulin, sulfonylurea (SUs) and DPP4Is head-to-head, there was no association with ACM in all comparisons (Tables 3.2 and S7.5) [32]. Against OADs + insulin, there was an associated reduction for ACM (Tables 3.3 and S7.3) [26].
For exenatide, two studies were associated with a reduction in ACM [26, 34], and one showed no association [35]. Versus non-exposure, the associated reduction in ACM was irrespective of baseline BMI, CVD status and BP (Tables 3.1 and S7.1) but a greater associated benefit was seen in those with more DM complications and in older people (DNS) [34]. Versus OADs and insulin, there was an associated reduction in ACM (Tables 3.3 and S7.3) [26]. Finally, versus the unexposed, there was no association with ACM (Tables 3.4 and S7.2) [35].
For liraglutide, all three studies were associated with a reduced risk of ACM, two vs. OAD [26, 34] and one vs. DPP4I [23] (Tables 3.1 [34], 3.3 [26], 3.5 [23], and S7.1 [34], S7.3 [26], S7.4 [23]). In one study there was also an associated reduction in CV death (Tables 3.5 and S7.4) [23]. For another, this was irrespective of baseline BMI, CVD status and BP but a greater associated benefit was shown in those with more DM complications and in older people (DNS) [34].
Pancreatic Outcomes
We found eight studies reporting the association of GLP1RAs with pancreatic outcomes, seven vs. OADs/usual care [14, 16, 18, 19, 22, 25, 28] and one as an self-controlled case series (SCCS) [30].
Acute Pancreatitis
We found seven studies that explored acute pancreatitis (AP) following GLP1RA exposure [15, 16, 18, 22, 25, 28, 30], five for exenatide [15, 22, 25, 28, 30] and two for liraglutide [16, 18] (Fig. 2).
Acute pancreatitis forest plot
For exenatide, four studies showed no association with AP following exposure (Tables 4.1 [28] and S8.1, 4.3 [25] and S8.3, 4.4 [22] and S8.4, 4.5 [30] and S8.5); in one study when ‘out-of-pocket’ expenses were used as a ‘quasi-randomised’ variable, there remained no association for AP [22]. Another study suggested an associated reduction in AP (Tables 4.2 and S8.2) [15]. When time post-exposure was considered, the same study showed an associated increase in AP with past exenatide use [15], but a different study suggested an associated reduction for past exposure (Tables 4.3 and S8.3) [25]. In the case of an SCCS, although throughout the study the associated effect of exenatide on both recurrent (DNS) and incident AP increased over time following exposure (as did both bounds of the 95% CIs), the effect estimates did not reach statistical significance (Tables 4.5 and S8.5) [30].
For liraglutide, two studies showed no associated with AP (Tables 4.7 [16] and S8.6, 4.8 [18] and S8.7). In one of these studies, there remained no association for AP in both the intention-to-treat (ITT) and on-treatment analysis [18].
Pancreatic Cancer
We found four studies that explored pancreatic cancer incidence following GLP1RA exposure, two for exenatide [14, 19, 22] and two for liraglutide [16, 18] (Fig. 3).
Pancreatic cancer forest plot
For exenatide, two studies showed no association following exposure (Tables 4.4, S8.4 and Tables 4.6, S8.8, the latter in the main cohort, cumulative response and nested case–control analyses) [14, 19, 22].
For liraglutide, two studies showed no association in all analyses (Tables 4.7 [18] and S8.6, 4.8 [16] and S8.7). In one of these there was no association for pancreatic cancer (PC) in both the ITT and on-treatment analysis in the 2014 study [18].
Thyroid Cancer
No study we found explored medullary thyroid cancer (MTC) (the specific cancer type putatively associated with GLP1RA exposure, Table 1). The only study identified reported no association with the risk of TC (which included, but was not limited to, MTC) with exenatide exposure, vs. OAD, in the main cohort and the cumulative dose–response analysis, nor the nested case control study (Tables 5.1 and S9.1) [14, 19].
Renal Outcomes
Only one study described renal outcomes, which suggests that exenatide exposure (vs. sitagliptin) was not associated with an increased time-to-renal-failure or acute renal failure (ARF), in which the majority of participants did not have baseline CKD (Tables 6.1 and S10.1) [21].
Diabetic Retinopathy
The one study we identified showed no association of GLP1RA class (vs. more than two OADs) on diabetic retinopathy (DR) incidence in those without pre-existing eye disease (Tables 7.1 and S11.1) [27]. No effect modification was detected by duration of DM treatment or baseline HbA1c but there was an increased risk of DR in those with hypertension and in those already on an angiotensin-converting enzyme inhibitor (ACEI).
Breast Cancer
The two studies we identified assessing the effect of GLP1RA exposure on breast cancer (vs. DPP4I [29], Tables 8.1 and S12.1 and vs. OAD [17], Tables 8.2 and S12.2) showed that both the GLP1RA class overall and the specific agents liraglutide and exenatide were associated with a neutral effect on risk of incident breast cancer, consistent in the duration response and ITT analyses in both studies overall [17, 29], apart from an associated transient increased risk at more than 3.1 years to less than 4 years in one [29].
Hypoglycaemia
We found three studies exploring rates of severe hypoglycaemia, two investigating exenatide exposure (Tables 9.2 [31] and S13.1, and 9.3 [20]) and one the GLP1RA class overall (Tables 9.1 [24] and S13.2). All studies used an insulin comparator group (as opposed to OAD) and showed no association with hypoglycaemia risk [20, 24, 31].
Discussion
Summary of Key Findings
For context, Table 1 gives a summary of the RCT (or other source of) evidence for the outcomes described in this review. Notably, of the individual GLP1RA agents, only studies exploring exenatide and liraglutide were found (because these have been available longest). Consequently, there is a need to undertake large observational studies of newer GLP1RA drugs (dulaglutide, semaglutide and lixisenatide). This discussion is, consequently, mainly limited to the GLP1RA class as a whole, exenatide and liraglutide.
Effectiveness
Cardiovascular Disease
For the GLP1RA class, studies either showed no association [32, 34] or an associated reduction [26] with CVD. These studies appear to confirm CVD safety for the GLP1RA class overall.
For exenatide, two studies reported an associated reduction for CVD [13, 33] and two studies reported no association [26, 35]. While these data confirm CVD safety, given that the cardiovascular outcome trial (CVOT) for exenatide did not show a reduction in CVD, exenatide should not be prescribed for the purposes of reducing CVD in people with T2D.
For liraglutide, two studies demonstrated an associated reduction for CVD [23, 26]. These findings first confirm CVD safety, but since liraglutide reduced MACE in the CVOT, they also confirm and extend these findings to those living with T2D but with a broader CV risk profile than those at elevated CV risk included in the CVOT for enrichment purposes.
Mortality
For the GLP1RA class, two studies showed an associated reduction in ACM [26, 34] and one showed no association [32]. No studies explored CV death.
For exenatide two studies were associated with a reduction in ACM [26, 34] and another showed no association [35]. No studies explored CV death. EXenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) showed nominally significant reduction in ACM (but not for CV death) [3]; for ACM these studies appear to suggest that exenatide may be associated with mortality postponement in a broad population and certainly does not appear to increase morality risk.
For liraglutide, all three studies demonstrated an associated reduction for ACM [23, 26, 34] and one study also showed a reduction in CV death [23]. LEADER showed a reduction in ACM and CV death [6]; for both these outcomes the studies we found appear to confirm that liraglutide may be associated with a postponement of both ACM and CV death in these broad populations.
Safety
The current regulatory position for GLP1RA safety is as follows. The European Medicines Agency (EMA) has issued a class-wide warning for AP [37] and specifically for semaglutide, for worsening of DR [38]. For semaglutide only, the US Food and Drug Administration (FDA) warns of worsening of DR, particularly in those already treated with insulin [39]. The FDA has issued class-wide warnings for AP and PC [40], for MTC [39], for ARF [39] and recently for hypoglycaemia in the context of co-prescription with Sus [39]. The Medicines and Healthcare products Regulatory Agency (MHRA) has recently warned about diabetic ketoacidosis (DKA) in the context of rapid insulin dose-reduction following GLP1RA initiation [41]. Not all of the agents/outcomes are addressed by studies included in this review.
Acute Pancreatitis
Seven studies explored this outcome [15, 16, 18, 22, 25, 28, 30]. For exenatide, four studies suggest no association [22, 25, 28, 30] and one an associated reduction [15]. For liraglutide all studies reported no association [16, 18]. In summary, the studies we found do not suggest that GLP1RAs (as a class or individual agent) are associated with AP.
Pancreatic Cancer
Four studies explored this outcome [16, 18, 19, 22]. For exenatide there was no association [19, 22]. For liraglutide both studies suggest no association for this outcome [16, 18]. Overall, these findings provide reassurance that neither the class overall nor the individual agents examined appear to be associated with PC over longer-term exposure.
Thyroid Cancer
One study explored this outcome [14, 19], which suggests no association for exenatide exposure for this outcome (for TCs in general and not MTC specifically). It is difficult to draw conclusions from a single study and this outcome should be investigated further.
Renal Outcomes
One study explored the association of exenatide with ARF [21]. Exposure did not appear to be associated with time-to-ARF and appears safe from the renal perspective. None of the outcomes trials explored renal events as a primary outcome (and were not reported in EXSCEL), although a secondary analysis of LEADER suggests that liraglutide exposure caused a reduction in the renal composite outcome (new-onset persistent microalbuminuria, persistent doubling of the serum creatinine level, ESRD, or death due to renal disease) driven mainly by a reduction in persistent microalbuminuria [3, 5, 42]. However, exenatide is renally excreted and should not be used in those with pre-existing renal impairment [43].
Diabetic Retinopathy
One study explored GLP1RA class exposure on DR and was associated with a neutral effect on this outcome (except a transient increase in risk at 6–12 months) [27]. It is difficult to draw conclusions from a single study and this outcome ought to be investigated further. In those with pre-existing eye disease caution should be employed and, in particular, slow titration should be considered to avoid rapid correction of hyperglycaemia which may precipitate DR.
Breast Cancer
Two studies explored this outcome [17, 29]. One study showed no association with breast cancer for the GLP1RA class overall, for exenatide and for liraglutide (except a transient increased in risk at 3–4 years) [29]. The other study showed no association for liraglutide [17]. These data appear to suggest that GLP1RA agents are not associated with an increased risk for this outcome.
Hypoglycaemia
Three studies explored this outcome [20, 24, 31]. For the GLP1RA class and for exenatide, the studies showed no association of exposure with hypoglycaemia (compared to insulin). GLP1RAs alone do not appear to increase the risk of hypoglycaemia, but may increase hypoglycaemia risk when co-prescribed with other drugs known to cause low blood glucose [39]. Given that the studies identified were compared directly to insulin use (and not co-prescription with insulin), these data do not shed light on this important question.
Strengths and Limitations
To our knowledge, this is the first systematic review to assess population-based observational studies looking at the effectiveness and safety of GLP1RA agents in T2D. We searched a large number of studies and involved a University of Edinburgh informationist to use appropriate search terms to ensure we captured the largest possible number of studies. We present data from many different countries and diverse populations of people living with T2D and the quality of the included papers is reported.
Importantly, some outcomes, particularly pancreatic disease, were assessed by combining GLP1RA and DPP4I exposure by assuming a common ‘incretin’ pathway leading to these pathologies (e.g. Singh et al. [44]). These studies, where it was not possible to discern an effect estimate for a GLP1RA agent alone, were prospectively excluded from this review (Table S2).
A major challenge was the variety of composite endpoints in the studies identified, particularly for CVD, making direct comparisons difficult. While composite primary endpoints is useful for increasing the power of a study to detect change (by increasing the events counted towards the primary endpoint) it would be helpful if future studies emulated the composite outcomes reported in the cardiovascular outcomes trials. This would be useful for comparing identified studies to each other and also to RCT data.
CVOTs have shown that liraglutide, subcutaneously administered semaglutide and dulaglutide reduce MACE [2, 6, 7]. Given that the last two agents have been licensed more recently, we did not identify population-based studies exploring these agents. It will be important to assess these agents’ effects on CVD in day-to-day clinical practice once sufficient person-time exposure has accumulated to allow for such analyses.
We deliberately excluded disproportionality reporting ratio studies based on interrogating adverse event reporting databases because of the high risk of bias, especially once an adverse event becomes known. However, gastroesophageal reflux-like symptoms [45] and intestinal obstruction [46] both emerged as potential harms from these studies and should be investigated further.
As with all observational data exploring treatment effectiveness, the studies included may be subject to unmeasured confounding and bias, particularly measurement/misclassification bias. Using population-based studies reduces the effect of selection bias but observational pharmacoepidemiology is always subject to confounding-by-indication, although most of the included studies used modern methods of controlling for this (e.g. propensity score matching, PSM). It remains the case that despite adequate study design and analysis methods, the associations described might be entirely explained away, or even reversed, by bias and confounding, particularly unmeasured confounding.
Notwithstanding considerable effort on our part to identify eligible studies systematically (including the manual searching of references), it remains possible that we overlooked potentially suitable studies and we omitted non-English language publications as a result of resource issues; thus, our findings may be affected by publication bias, which we could not measure using a funnel plot because of insufficient numbers of studies. Although the search terms we employed should detect observational studies conforming to the Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) items on publication title and abstract, studies not conforming would be missed (but non-conforming could be considered a marker of poor quality at any rate).
We did not use meta-analytic methods in this review because of axiomatic breaches of the methodology, including significant study diversity and possible double counting of outcome events.
Conclusions
This work provides broadly generalisable effectiveness estimates in more heterogeneous populations than those included in CVOTs. Our study confirms that GLP1RAs, either as a class or as individual agents, do not appear to be associated with an increased risk of CV events and are safe from this perspective. For liraglutide, our review confirms and extends trial findings that this agent appears to be associated with a reduction in CV events of similar direction and order of magnitude to the CVOT.
The included studies did not find evidence of previously reported safety outcomes, although some outcomes were only explored in a single study (or a small number of studies). GLP1RAs do not appear to be associated with pancreatic pathology, TC, worse renal outcomes (in those without baseline CKD), incident DR (in those without baseline DR), incident breast cancer and displayed a decreased or no association on the risk of hypoglycaemia (when compared to insulin/OAD respectively). Given the heterogeneity of the studies in terms of outcome definition, population, confounding control and analysis method, making generalised conclusions about these data is challenging.
These data will be of use to people living with T2D, their clinicians, medical regulators and guideline-writing organisations and should be updated as more data become available.
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Acknowledgements
We would like to thank Ruth Jenkins at the University of Edinburgh Library. TC acknowledges the support of Diabetes UK (‘Sir George Alberti’ Clinical Research Training Fellowship 18/0005786). RMR acknowledges the support of the British Heart Foundation (RE/18/5/34216).
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No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
TMC and JBT conceived, designed and executed this study. TAC provided critical manuscript revision and restructuring figure and table construction and approved the final version. SHW and RMR critically reviewed the draft manuscript and approved the final version. DJW provided manuscript review/editing, expert clinical pharmacology opinion and research supervision. HMC provided expert pharmacoepidemiology opinion and research supervision.
Disclosures
Thomas M. Caparrotta, Jack B. Templeton, Thomas A. Clay, Sarah H. Wild, Rebecca M. Reynolds, David J. Webb, Helen M. Colhoun report disclosures or no conflicts of interest.
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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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All data generated or analysed during this study are included in this published article/as supplementary information files.
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Caparrotta, T.M., Templeton, J.B., Clay, T.A. et al. Glucagon-Like Peptide 1 Receptor Agonist (GLP1RA) Exposure and Outcomes in Type 2 Diabetes: A Systematic Review of Population-Based Observational Studies. Diabetes Ther 12, 969–989 (2021). https://doi.org/10.1007/s13300-021-01021-1
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DOI: https://doi.org/10.1007/s13300-021-01021-1