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Aim: We aimed to investigate the long‐term impact of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). Materials and Methods: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP‐1 RA treatment and those who did not receive glucose‐lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. Results: After propensity score matching, the study included 12,123 individuals in each group. GLP‐1 RA treatment was associated with a significantly lower risk of all‐cause mortality (hazard ratio 0.23; 95% confidence interval 0.15–0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP‐1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. Conclusions: In this large observational study, GLP‐1 RAs showed long‐term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP‐1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population. [ABSTRACT FROM AUTHOR]

Aim: Glucagon‐like peptide 1 receptor agonists (GLP1RA) and sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown. Methods: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new‐onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non‐DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD. Results: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non‐DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre‐existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01‐2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups. Conclusions: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use. [ABSTRACT FROM AUTHOR]

Aim: To synthesize the evidence on the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in adolescents with overweight or obesity. Materials and Methods: For this systematic review and network meta‐analysis, we searched five databases and registries until 2 March 2024 for eligible randomized controlled trials (RCTs). The primary outcome was weight change. We did a pairwise meta‐analysis to compare GLP‐1RAs and placebo, followed by a drug‐wise network meta‐analysis (NMA) to compare GLP‐1RAs against each other. Results: We screened 770 records to include 12 RCTs with 883 participants. The evidence suggests that GLP‐1RAs reduced weight (mean difference −4.21 kg, 95% confidence interval [CI] −7.08 to −1.35) and body mass index (BMI; mean difference −2.11 kg/m2, 95% CI −3.60 to −0.62). The evidence on waist circumference, body fat percentage and adverse events (AEs) was very uncertain. The results remained consistent with subgroup analyses for coexisting type 2 diabetes. Longer therapy duration led to a greater reduction in weight and BMI. In the NMA, semaglutide led to the greatest weight reduction, followed by exenatide, liraglutide and lixisenatide. Conclusions: The evidence suggests that GLP‐1RAs reduce most weight‐related outcomes in adolescents, with semaglutide being the most efficacious. There is uncertain evidence on body fat and serious AEs, probably due to fewer studies and low incidence, respectively. Larger RCTs with head‐to‐head comparisons, pragmatic design, adiposity‐related outcomes, and economic evaluation can further guide the use and choice of GLP‐1RAs. [ABSTRACT FROM AUTHOR]

Aim: To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon‐like peptide‐1 receptor agonists [GLP‐1RAs] vs. non‐GLP‐1RAs) after bariatric surgery. Methods: This single‐centre retrospective cohort included patients (aged 16–65 years) who had undergone laparoscopic Roux‐en‐Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)‐approved, off‐label, or GLP‐1RA AOMs if documented as receiving the medication on or after cohort entry date. Non‐GLP‐1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP‐1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs. Results: We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9–55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP‐1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5–2.6) and aOR 1.1 (95% CI 0.6–2.3) for GLP‐1RA versus FDA‐approved and off‐label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0–0.01]; p < 0.001). Conclusion: Our results showed that GLP‐1RA AOMs were not associated with an increased risk of AEs compared to non‐GLP‐1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP‐1RA initiation. [ABSTRACT FROM AUTHOR]

Aim: To compare the effectiveness of different basal insulins (BI) prescribed as an add‐on to or switch from glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) therapy. Materials and Methods: Retrospective, real‐world data from electronic medical records of 32 Italian diabetes clinics were used, after propensity score adjustment, to compare effectiveness after 6 months of treatment with second‐ versus first‐generation BI (2BI vs. 1BI) or glargine 300 U/ml versus degludec 100 U/ml (Gla‐300 vs. Deg‐100), when added to (ADD‐ON) or in substitution of (SWITCH) GLP‐1 RA. Only comparisons, including a minimum of 100 patients per group, were performed to ensure adequate robustness of the analyses. Results: In the ADD‐ON cohort (N = 700), greater benefits of 2BI versus 1BI were found in glycated haemoglobin {HbA1c; estimated mean difference: −0.32% [95% confidence interval (CI) −0.62; −0.02]; p =.04} and fasting blood glucose [FBG; −20.73 mg/dl (95% CI −35.62; −5.84); p =.007]. In the SWITCH cohort (N = 2097), greater benefits of 2BI versus 1BI were found in HbA1c [−0.22% (95% CI −0.42; −0.02); p =.03], FBG [−10.15 mg/dl (95% CI −19.04; −1.26); p =.03], and body weight [−0.67 kg (95% CI −1.30; −0.04); p =.04]. In the SWITCH cohort starting 2BI (N = 688), marked differences in favour of Gla‐300 versus Deg‐100 were documented in HbA1c [−0.89% (95% CI −1.26; −0.52); p <.001] and FBG [−17.89 mg/dl (95% CI −32.45; −3.33); p =.02]. Using propensity score matching as a sensitivity analysis, the benefit on HbA1c was confirmed [−0.55% (95% CI –1.02; −0.08); p =.02]. BI titration was suboptimal in all examined cohorts. Conclusions: 2BI are a valuable option to intensify GLP‐1 RA therapy. Switching to Gla‐300 versus Deg‐100 was associated with greater HbA1c improvement. [ABSTRACT FROM AUTHOR]

Aims: To conduct a meta‐analysis of randomized controlled trials (RCTs) to evaluate the effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) metrics as an adjunct to insulin therapy in adults with type 1 diabetes mellitus (T1D). Methods: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library, and Google Scholar up to 27 May 2024. Dual‐independent study selection, data extraction, and quality assessment were performed. Results were summarized using random‐effects meta‐analysis. Results: Six RCTs were identified, involving a total of 378 individuals with T1D. The use of GLP‐1RAs in addition to standard insulin therapy was associated with a significant reduction in HbA1c (mean difference [MD] −0.21%, 95% confidence interval [CI] −0.36 to −0.06; p = 0.007) and a similar time in range (TIR) compared to placebo (MD −0.22%, 95% CI −2.39 to 1.95; p = 0.84). GLP‐1RA therapy resulted in a significantly higher time below range (MD 1.13%, 95% CI 0.50 to 1.76; p < 0.001) and a lower time above range compared with placebo (MD −1.83%, 95% CI −2.51 to −1.15; p < 0.001). Nonsignificant differences were noted for the secondary outcomes, including the mean amplitude of glucose excursion, continuous overall net glycaemic action for 60 min, mean daily glucose, coefficient of variation, and mean standard deviation of weekly glucose levels. Conclusion: Our findings suggest that, in individuals with T1D, add‐on therapy with GLP‐1RAs does not confer significant benefits in terms of CGM metrics and is associated with a longer time below the target glycaemic range. [ABSTRACT FROM AUTHOR]

Aim: Sodium‐glucose cotransporter 2 inhibitors (SGLT2is) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) improve glycaemic control and cardio‐renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio‐economic variation in use is not well understood. Methods: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose‐lowering medicines among people with T2D and the prevalence of SGLT2i and GLP‐1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose‐lowering medicine). We measured the prevalence by small‐level geography, stratified by age group, and characterized by remoteness and socio‐economic status. Results: The prevalence of SGLT2i (29.7%) and GLP‐1RA (8.3%) use in people with T2D aged 40‐64 increased with geographic remoteness and in areas of greater socio‐economic disadvantage, similar to other glucose‐lowering medicines. The prevalence of SGLT2i (55.4%) and GLP‐1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP‐1RA use (2.5 times the median). Compared with people aged 40‐64 years, the prevalence of SGLT2i and GLP‐1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. Conclusions: The prevalence of SGLT2i and GLP‐1RA use varied by geography, probably reflecting a combination of system‐ and prescriber‐level factors. Socio‐economic variation in GLP‐1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most. [ABSTRACT FROM AUTHOR]

Aim: The cardiovascular benefits provided by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP‐lowering effects of GLP1‐RAs. Methods: A comprehensive database search for placebo‐controlled randomized controlled trials on GLP‐1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta‐regressions were done to account for covariates. Results: Compared with placebo, GLP‐1RAs modestly reduced SBP [semaglutide: MD −3.40 (95% CI −4.22 to −2.59, p <.001); liraglutide: MD −2.61 (95% CI −3.48 to −1.74, p <.001); dulaglutide: MD −1.46 (95% CI −2.20 to −0.72, p <.001); and exenatide: MD −3.36 (95% CI −3.63 to −3.10, p <.001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD −0.94 (95% CI −1.78 to −0.1), p =.03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. Conclusion: Patients on GLP‐1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP‐lowering is an indirect effect of GLP‐1RA and unlikely to be responsible for the benefits. [ABSTRACT FROM AUTHOR]

Aim: Using a systematic review and meta‐analysis of placebo‐controlled cardiovascular outcome trials (CVOTs) of newer glucose‐lowering agents [sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and dipeptidyl peptidase‐4 inhibitors (DPP‐4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. Materials and Methods: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study‐specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta‐regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. Results: Twenty unique CVOTs (six SGLT‐2is, nine GLP‐1RAs, five DPP‐4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT‐2is, GLP‐1RAs and DPP‐4is with placebo, the hazard ratios (95% CIs) for 3‐point major adverse cardiovascular events were 0.88 (0.82‐0.94), 0.85 (0.79‐0.92) and 1.00 (0.94‐1.06), respectively. SGLT‐2is and GLP‐1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP‐4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3‐point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67‐1.06; p =.14; R2 = 14.2%), which was driven by the component of non‐fatal stroke (R2 = 100.0%; p =.094). There were non‐significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. Conclusions: SGLT‐2is and GLP‐1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT‐2is and GLP‐1RAs in patients with T2D extend beyond mere glycaemic control. [ABSTRACT FROM AUTHOR]

Aim: To conduct a meta‐analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) treatment and thyroid cancer. Materials and Methods: In this meta‐analysis of RCTs, we included studies comparing a GLP‐1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. Results: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP‐1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel‐Haenzel odds ratio [MH‐OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5‐year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH‐OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH‐OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH‐OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). Conclusions: Our meta‐analysis showed that GLP‐1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding. [ABSTRACT FROM AUTHOR]

Aims: The objective of this umbrella review and meta‐analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. Materials and Methods: We conducted a systematic umbrella review on diabetes and its treatment, and a meta‐analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta‐analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random‐effects meta‐analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon‐like peptide‐1 receptor agonists (GLP1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) with risk of dementia from cohort/case‐control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle‐Ottawa Scale. Results: We included 100 reviews and 27 cohort/case‐control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. Conclusions: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted. [ABSTRACT FROM AUTHOR]

Aim: To report health‐related patient‐reported outcomes (PROs) in people with type 2 diabetes (T2D) initiating their first injectable glucose‐lowering medication (GLM) with two commonly prescribed glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) from the prospective, observational TROPHIES study (The Real‐World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients). Materials and Methods: TROPHIES was a two‐cohort, 24‐month study conducted in France, Germany and Italy. Adults with a T2D diagnosis, naïve to injectable treatment for T2D and prescribed dulaglutide or liraglutide as their first injectable GLM, were eligible for inclusion. Study objectives included describing the following PROs associated with the treatment of T2D with GLP‐1RAs: health‐related quality of life; impact of weight on self‐perception; life and work productivity; and patient satisfaction with treatment and injection device. Additional analyses formally compared PRO measures between the treatment cohorts. Results: Overall, improvements from baseline in PRO scores were observed among people who started dulaglutide or liraglutide. A more pronounced trend of improvement was observed in the dulaglutide cohort for changes from baseline in treatment satisfaction and impact of weight on self‐perception, supported by statistically significant differences between treatment cohorts in additional comparative analyses at 12, 18 and 24 months. More positive patient perceptions of the injection device were observed with dulaglutide than with liraglutide. Conclusions: Improvements in PROs observed in TROPHIES, which were more evident with dulaglutide than liraglutide, reflect a relevant clinical benefit. From the patients' perspective, satisfaction, and confidence in continuing treatment with GLP‐1RAs is likely to contribute to long‐term treatment persistence. [ABSTRACT FROM AUTHOR]

Aim: To assess the relationship of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor analogues (GLP‐1RA) and their combination (SGLT2i + GLP‐1RA) with 5‐year risk of all‐cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes. Materials and Methods: Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP‐1RA and SGLT2i + GLP‐1RA) were compared against a control cohort (no SGLT2i/GLP‐1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP‐1RA, n = 186 841; SGLT‐2i + GLP‐1RA, n = 108 504). A sub‐analysis comparing combination and monotherapy cohorts was also performed. Results: The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all‐cause mortality (SGLT2i 0.49, 0.48‐0.50; GLP‐1RA 0.47, 0.46‐0.48; combination 0.25, 0.24‐0.26), hospitalization (0.73, 0.72‐0.74; 0.69, 0.68‐0.69; 0.60, 0.59‐0.61) and acute myocardial infarct (0.75, 0.72‐0.78; 0.70, 0.68‐0.73; 0.63, 0.60‐0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub‐analysis showed a significant risk reduction in all‐cause mortality for combination therapy versus SGLT2i (0.53, 0.50‐0.55) and GLP‐1RA (0.56, 0.54‐0.59). Conclusions: SGLT2i, GLP‐1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all‐cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5‐year all‐cause mortality when compared directly against either monotherapy. [ABSTRACT FROM AUTHOR]

Aims: To perform a meta‐analysis to assess the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on major coronary events, including myocardial infarction (MI), unstable angina and coronary revascularization, in patients with type 2 diabetes mellitus (T2DM). Materials and methods: We systematically searched the PubMed, CENTRAL, EMBASE and clinicaltrial.gov databases to seek eligible studies with a cardiovascular endpoint comparing GLP‐1RAs with a placebo in T2DM patients. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated for the outcomes. Results: Nine studies, with a total of 64 236 patients, were included. GLP‐1RA treatment reduced fatal and nonfatal MI by 8% (OR 0.92, 95% CI 0.86–0.99; P = 0.02, I2 = 39%). The reduction reached 15% in human‐based GLP‐1RA‐treated patients. Similarly, once‐weekly GLP‐1RA treatment reduced the risk of MI by 13%. In contrast, GLP‐1RA treatment did not reduce the risk of hospitalization for unstable angina (OR 1.11, 95% CI 0.97–1.28; P = 0.13, I2 = 21%). GLP‐1RAs exhibited a tendency to lower the risk of coronary revascularization (OR 0.95, 95% CI 0.89–1.02; P = 0.15, I2 = 22%), but without statistical significance. Human‐based GLP‐1RAs decreased the risk by 11%. Conclusions: In high‐risk patients with T2DM, GLP‐1RAs were associated with a decrease in MI, especially the human‐based and once‐weekly GLP‐1RAs. No benefit was seen for hospitalization for unstable angina or coronary revascularization. Further research is urgently needed to ascertain improvements in coronary events. [ABSTRACT FROM AUTHOR]

Aim: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. Materials and Methods: A nationwide, population‐based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non‐insulin, glucose‐lowering drug. Results: The rate of new users of non‐insulin, glucose‐lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020‐2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose‐lowering drug consumption, followed by insulin (17%), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) (17%), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) (16%) and dipeptidyl peptidase‐4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose‐lowering drugs. Marked shifts towards GLP‐1RA initiation by general practitioners and SGLT‐2i initiation by specialists were observed, and changing user profiles suggested increasing use for non‐diabetes indications. Conclusions: The rate of new users of non‐insulin, glucose‐lowering drugs has increased in recent years and the prevalence of glucose‐lowering drug use increases steadily. Glucose‐lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose‐lowering treatment are increasing. [ABSTRACT FROM AUTHOR]

Aims: To conduct a systematic review and network meta‐analysis to determine the comparative effectiveness of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors in patients with diabetic kidney disease (DKD). Methods: Phase III or IV randomized, placebo‐controlled trials evaluating SGLT2 inhibitors, GLP‐1RAs or DPP‐4 inhibitors in patients with DKD were identified from the MEDLINE database. The outcomes of interest were a kidney‐specific composite outcome, kidney disease progression, major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF) and cardiovascular death. A network meta‐analysis was conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Sixteen trials representing a total of 46 292 patients were included. SGLT2 inhibitors significantly reduced the risk of the kidney‐specific composite outcome by 26% compared to GLP‐1RAs (HR 0.74, 95% CI 0.62‐0.88) and by 36% compared to DPP‐4 inhibitors (HR 0.64, 95% CI 0.52‐0.79). The risk of MACE was significantly reduced with SGLT2 inhibitors (by 18%; HR 0.82, 95% CI 0.72‐0.93), and with GLP‐1RAs (by 18%; HR 0.82, 95% CI 0.69‐0.96), compared to DPP‐4 inhibitors. SGLT2 inhibitors significantly reduced the risk of HHF by 28% compared to GLP‐1RAs (HR 0.72, 95% CI 0.56‐0.92) and by 41% compared to DPP‐4 inhibitors (HR 0.59, 95% CI 0.49‐0.71). Conclusions: A clear advantage was demonstrated by SGLT2 inhibitors in reducing the risks of CV and renal events in patients with DKD, compared to GLP‐1RAs and DPP‐4 inhibitors. We recommend that SGLT2 inhibitors be considered the treatment of choice in patients with DKD. [ABSTRACT FROM AUTHOR]

Aim: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once‐weekly subcutaneous dulaglutide versus placebo. Materials and Methods: Patients without electrocardiographic (ECG)‐confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. Results: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow‐up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person‐years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person‐years (P =.59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. Conclusion: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at‐risk group of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effects of separate and combined use of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor dapagliflozin and the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) exenatide on measures of kidney function. Methods: In this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16‐week randomized double‐blind placebo‐controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24‐hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C‐estimated glomerular filtration rate (GFR) and kidney injury molecule‐1:creatinine ratio (KIM‐1:Cr). Results: At week 16, the mean UACR change from baseline was −39.6% (95% confidence interval [CI] −58.6, −11.9; P = 0.001) in the combined exenatide‐dapagliflozin group, −18.1% (95% CI −43.1, 18.0; P = 0.278) in the dapagliflozin group, −15.6% (95% CI −41.4, 21.6; P = 0.357) in the exenatide group and − 11.0% (95% CI −39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide‐dapagliflozin group was −32.2% (95% CI −60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide‐dapagliflozin group, an acute dip in estimated GFR was observed with creatinine‐estimated GFR (−4.0 mL/min/1.73 m2 [95% CI −9.3, 1.2]; P = 0.129) and cystatin C‐estimated GFR (−10.4 mL/min/1.73 m2 [95% CI −14.9, −5.8]; P < 0.001). The mean KIM‐1:Cr difference in the combined treatment arm versus placebo was −43.8% (95% CI −73.5, 18.9; P = 0.129). Conclusion: This prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To conduct a meta‐analysis and systematic review to examine the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on clinical biomarkers of inflammation and oxidative stress in patients with type 2 diabetes. Methods: Medline, Embase and the Cochrane Library were searched for randomised controlled trials (RCTs) that examined changes with GLP‐1RAs in a priori selected biomarkers of inflammation: C‐reactive protein (CRP), adiponectin, tumour necrosis factor‐alpha (TNFα), plasminogen activator inhibitor‐1, interleukin‐6, leptin; and of oxidative stress: malondialdehyde (MDA); 8‐iso‐prostaglandin F2α; and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG). Results: We included 40 eligible RCTs (n = 6749) with a median follow‐up of 6 months, a mean participant age of 53.1 years, 56.3% females, glycated haemoglobin (HbA1c) 55.6 mmol/mol, body mass index 28.8 kg/m2 and diabetes duration 7.46 years. Analysis of GLP‐1RAs versus standard diabetes therapies or placebo revealed significant reductions in CRP, TNFα and MDA, and significant increases in adiponectin for (mean difference −0.54 mg/L [−0.75, −0.34]; standard mean difference [SMD] −0.39 [−0.62, −0.15]; SMD −0.84 [−1.61, −0.06] and SMD 0.30 [0.12, 0.49], respectively [95% confidence intervals]). Systolic blood pressure decreased significantly and was significantly and strongly correlated with a reduction in CRP. Homeostatic model assessment of insulin resistance was also significantly correlated with a reduction in CRP, but HbA1c was not. Conclusions: There is strong evidence supporting clinically relevant anti‐inflammatory and antioxidant effects of GLP‐1RAs. This may be used to guide future targeted clinical use of GLP‐1RAs and the development of medications seeking to target the cardioprotective properties of GLP‐1RAs. [ABSTRACT FROM AUTHOR]

Aim: To examine the efficacy and safety of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 (SGLT2) inhibitors compared with other antihyperglycaemic agents (AHAs) in large and unselected populations of the Lombardy and Apulia regions in Italy. Materials and Methods: An observational cohort study of first‐time users of GLP‐1RAs, SGLT2 inhibitors or other AHAs was conducted from 2010 to 2018. Death and cardiovascular (CV) events were evaluated using conditional Cox models in propensity‐score‐matched populations. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each region and in a meta‐analysis for pooled risks. Results: After propensity‐score matching, the Lombardy cohort included 18 716 and 11 683 patients and the Apulia cohort 9772 and 6046 patients for the GLP‐1RA and SGLT2 inhibitor groups, respectively. Use of GLP‐1RAs was associated with lower rates of death (HR 0.61, CI 0.56‐0.65, Lombardy; HR 0.63, CI 0.55‐0.71, Apulia), cerebrovascular disease and ischaemic stroke (HR 0.70, CI 0.63‐0.79; HR 0.72, CI 0.60‐0.87, Lombardy), peripheral vascular disease (HR 0.72, CI 0.64‐0.82, Lombardy; HR 0.80, CI 0.67‐0.98, Apulia), and lower limb complications (HR 0.67, CI 0.56‐0.81, Lombardy; HR 0.69, CI 0.51‐0.93, Apulia). Compared with other AHAs, SGLT2 inhibitor use decreased the risk of death (HR 0.47, CI 0.40‐0.54, Lombardy; HR 0.43, CI 0.32‐0.57, Apulia), cerebrovascular disease (HR 0.75, CI 0.61‐0.91, Lombardy; HR 0.72, CI 0.54‐0.96, Apulia), and heart failure (HR 0.56, CI 0.46‐0.70, Lombardy; HR 0.57, CI 0.42‐0.77, Apulia). In the pooled cohorts, a reduction in heart failure was also observed with GLP‐1RAs (HR 0.89, 95% CI 0.82‐0.97). Serious adverse events were quite low in frequency. Conclusion: Our findings from real‐world practice confirm the favourable effect of GLP‐1RAs and SGLT2 inhibitors on death and CV outcomes across both regions consistently. Thus, these drug classes should be preferentially considered in a broad type 2 diabetes population beyond those with CV disease. [ABSTRACT FROM AUTHOR]

The effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP‐1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once‐weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR. [ABSTRACT FROM AUTHOR]

Aims: To examine the albuminuria‐lowering effect of exenatide once weekly (EQW) compared with active glucose‐lowering comparators in patients with type 2 diabetes and elevated urinary albumin‐to‐creatinine ratio (uACR). Methods: Six randomized double‐blind and open‐label phase III studies were pooled in a post hoc, exploratory analysis to evaluate the efficacy and safety of EQW versus non‐glucagon‐like peptide‐1 receptor agonist comparators in patients with type 2 diabetes and baseline uACR ≥30 mg/g. Treatment groups were EQW versus all comparators pooled. Efficacy outcomes were percent change from baseline to week 26/28 in uACR and absolute change in glycated haemoglobin (HbA1c), systolic blood pressure (SBP), body weight and estimated glomerular filtration rate (eGFR). Results: Baseline characteristics were generally similar between the two treatment groups (EQW: N = 194, all comparators: N = 274). Relative to the comparator group, EQW changed albuminuria by −26.2% (95% confidence interval [CI] −39.5 to −10). Similar improvements were observed with EQW versus oral glucose‐lowering drugs (−29.6% [95% CI −47.6 to −5.3) or insulin (−23.8% [95% CI −41.8 to −0.2]). The effect of EQW on uACR was independent of baseline renin‐angiotensin system inhibitor usage. Adjusted mean decreases in HbA1c, SBP and body weight were more pronounced in the EQW versus the comparator group. Adjustment for changes in HbA1c, eGFR and SBP did not substantially affect the uACR‐lowering effect of EQW. When also adjusting for changes in body weight, the uACR‐lowering effect was reduced to (−13.0% [95% CI −29.9 to 7.8]). Conclusion: Exenatide once weekly reduced uACR in patients with type 2 diabetes and elevated albuminuria compared to commonly used glucose‐lowering drugs. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose‐lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end‐stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co‐morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population. [ABSTRACT FROM AUTHOR]

Aim: To conduct a meta‐analysis of cardiovascular outcome trials on the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on major adverse cardiovascular events (MACE). Methods: A search of MEDLINE, EMBASE, Cochrane database and clinicaltrials.gov was performed to identify controlled trials (up to 15 June 2019) of GLP‐1RAs with a cardiovascular endpoint. The principal endpoint of the present meta‐analysis was MACE; secondary endpoints included myocardial infarction, stroke, cardiovascular and all‐cause mortality, and hospitalization for heart failure. Mantel–Haenszel odds ratios (MH‐ORs) with 95% confidence intervals (CIs) were calculated for all outcomes. Results: In the seven trials included, all placebo‐controlled, GLP‐1RA treatment was associated with a reduction in MACE (MH‐OR 0.87 [95% CI 0.81, 0.93]). Cardiovascular and all‐cause mortality, myocardial infarction and stroke were also reduced (MH‐OR 0.88 [95% CI 0.80, 0.96], MH‐OR 0.90 [95% CI 0.82, 0.98], MH‐OR 0.91 [95% CI 0.84, 0.98] and MH‐OR 0.86 [95% CI 0.77, 0.97], respectively). Results for hospitalization for heart failure were not statistically significant (MH‐OR 0.93 [95% CI 0.83, 1.04]). The meta‐analyses of patient subgroups showed a significant reduction in MACE with GLP‐1RAs, irrespective of gender, advanced age and obesity. Conclusions: GLP‐1RAs are associated with a reduction in cardiovascular morbidity and mortality in high‐risk patients with diabetes. This effect does not appear to be moderated by gender or body mass index. The possibility of different effects of GLP‐1RAs between patients in primary and secondary prevention merits further investigation. [ABSTRACT FROM AUTHOR]

Aim To determine the association between the use of incretin agents (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) for the treatment of type 2 diabetes mellitus (T2DM) and the risk of any, acute and chronic pancreatitis. Research design and methods A population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD 2007-2012). A total of 182 428 adult patients with ≥1 non-insulin antidiabetic drug (NIAD) prescription were matched to control subjects without diabetes. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of pancreatitis in incretin-users (N = 28 370) compared with controls and with other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new-user design was used. Results Current incretin users had a 1.5-fold increased risk of any pancreatitis compared with NIAD users (adjusted HR 1.47, 95% CI 1.06-2.04). In incident current incretin users the risk of any and acute pancreatitis was increased 2.1- and 2.0-fold compared with NIAD users (adjusted HR 2.12, 95% CI 1.31-3.43 and adjusted HR 1.96, 95% CI 1.13-3.41), whereas there was no increased risk found for chronic pancreatitis. Conclusions Incretin use was associated with an increased risk of any pancreatitis. Moreover, risk of any and acute pancreatitis was higher when applying a new-user design. We were not able to detect an association with chronic pancreatitis, but the number in this subgroup was small. [ABSTRACT FROM AUTHOR]

Aims To investigate the effect of infusion of the glucagon-like peptide-1 ( GLP-1) receptor agonist exenatide on exocrine pancreatic function. Methods This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct ( PD) diameter were measured. Results Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. Conclusions Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion. [ABSTRACT FROM AUTHOR]

Aim To investigate the real-world incidence of acute pancreatitis ( AP) associated with incretin-based therapy ( IBT). Methods We carried out a systematic review and meta-analysis of observational studies using Medline, PubMed, Embase, the Cochrane Database, and conference proceedings. We included: those studies in which AP was a pre-defined clinical outcome; longitudinal studies (case-control, cohort); studies that adjusted for confounders; studies that reported on a population exposed to IBT; studies in which non- IBT users or past users (who received IBTs >90 days before the index date) were used as the control group; studies that reported risk estimates [relative risks, odds ratios ( ORs) or hazard ratios] with 95% confidence intervals ( CIs) for AP event with IBT use, or that reported sufficient data to estimate these; and publications in the English language. Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study-specific ORs from seven cohort studies and two case-control studies were meta-analysed using random-effects models. Associations were tested in subgroups representing different patient characteristics and study quality. Results A total of nine studies that included 1 324 515 patients and 5195 cases of AP were included in our meta-analysis. The summary estimate of OR for an association between IBT and AP was 1.03 (95% CI 0.87-1.20). Conclusions The present meta-analysis of real-world data does not suggest that IBT is associated with AP. Although we should continue to remain vigilant, IBTs should be regarded as reasonable options to consider adding to the regimen of a patient with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (≈20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and β-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum. [ABSTRACT FROM AUTHOR]

Aims To compare adherence (proportion of days covered [ PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus ( T2DM) newly initiating glucagon-like peptide-1 receptor agonists ( GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. Methods Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. Results Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P < .0001) and liraglutide (0.71 vs 0.67; P < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P < .0001) and liraglutide (53.5% vs 44.3%; P < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P < .0001) and those on liraglutide (28.0% vs 35.6%; P < .0001). Conclusions Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period. [ABSTRACT FROM AUTHOR]