GLP-1RA Use Research Articles

Impact of chronic GLP-1 receptor agonist and SGLT-2 inhibitor therapy on in-hospital outcomes of patients with diabetes mellitus hospitalized with acute myocardial infarction

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection in addition to their glucose-lowering effect. Whether their benefits occur also in patients with diabetes mellitus (DM) during hospitalisation with acute myocardial infarction (AMI) has not been investigated yet. Purpose We evaluated in-hospital outcomes of patients hospitalised with AMI according to their chronic use (before hospitalisation) of GLP-1 RA and SGLT-2i therapy. Methods Using administrative healthcare databases, we analysed patients hospitalised with a primary diagnosis of AMI from 2010 to 2019 in the Lombardy region, Italy. Patients were stratified according to their DM status, then divided into three cohorts: Group 1 (non-DM patients); Group 2 (DM patients taking GLP-1 RA or SGLT-2i); and Group 3 (DM patients not taking GLP-1 RA and/or SGLT-2i). Patients were matched in a 1:1:1 ratio using a propensity score including all available variables. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy. Results We identified 146,800 patients hospitalised with AMI (26% of them with DM). After propensity score matching, 1,030 patients were included in each group. The primary endpoint rate in the overall population was 16% (n=502) and it significantly increased going from Group 1 to Group 3 (13%, 16%, and 20% respectively; p for trend <0.0001). The risk of the composite endpoint significantly increased from Group 1 to Group 3 (P for trend <0.0001). In comparison with Group 2, Group 3 had a significant higher risk of the composite endpoint (OR 1.40 [95% CI 1.11–1.77]). Conclusions Our study shows that DM patients hospitalised with AMI and on chronic GLP-1 RA and/or SGLT-2i therapy have a better in-hospital clinical outcome than DM patients without them. Funding Acknowledgement Type of funding sources: None.

EE352 Projecting the Incidence and Costs of Major Cardiorenal Complications of Type 2 Diabetes with Widespread GLP-1 RA and SGLT2I Use

Whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or sodium-glucose co-transporter 2 inhibitors (SGLT2is) are cost-effective when considering solely their cardiorenal benefits is unknown. We projected the incidence and costs of hospitalisation for myocardial infarction (MI), stroke, and heart failure (HF), and end-stage kidney disease (ESKD) among people with type 2 diabetes under scenarios of widespread use of these drugs, from an Australian healthcare perspective.

Can glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help in mitigating the risk of atrial fibrillation in patients with diabetes?

The role of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in mitigating the risk of atrial fibrillation (AF) remains unknown. We interrogated the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database to study the association between AF-related adverse events and the use of GLP-1 RA and DPP-4i. A signal of disproportionate reporting of AF was detected with the DPP-4i group compared with all the other drugs in the FAERS database [ROR, 2.56; 95% confidence interval (CI), 2.10–3.12], whereas there was no disproportionality signal detected with the GLP-1 RA group (ROR, 0.90; 95% CI, 0.78–1.03) although liraglutide showed a significant disproportionality signal (ROR, 2.51; 95% CI, 2.00–3.15). Our analysis supports the existing body of literature demonstrating the cardiac safety of GLP-1 RA but raises concerns about the apparent increase in the risk of AF associated with DPP-4i. Further clinical and translational studies are needed to validate these findings.

107-LB: Progression of Position of Basal Insulin in the Treatment of Type 2 Diabetes—A Real-World Analysis

Background: In the past 5 years, type 2 diabetes practice guidelines have shifted to prioritize agents with cardiovascular (CV) and renal benefit. This study assessed whether real-world medication use has changed in line with these evolving guidelines. Methods: We retrospectively examined the treatment patterns (12 months pre and post) of people with T2D (PwT2D) who initiated basal insulin (BI) in either 2015 (cohort 1) , 2017 (cohort 2) , or 2019 (cohort 3) using IBM® MarketScan® Databases. Between-group differences were analyzed via t-test or chi-square as appropriate. Results: In the study period, 6,396,441 PwT2D were identified. The number of PwT2D initiating BI was 17,801/948,805 (1.88%) in 2015 vs. 10,870/622,455 (1.75%) in 2019 and a progressively larger share of BI initiators had prior GLP-1RA use (14.8% in cohort 1 vs. 25.2% in cohort 3; p < 0.001) or SGLT-2i use (11.4% in cohort 1 vs. 20.5% in cohort 3; p < 0.001) . Furthermore, in patients without prior GLP-1RA, SGLT-2i, or bolus use who initiated GLP-1RA or SGLT-2i in the first year of BI, time to first GLP-1RA (132.4 days in cohort 1 vs. 120.5 days in cohort 3; p = 0.02) or SGLT-2i (131.5 days in cohort 1 vs. 113.3 days in cohort 3; p = 0.002) decreased. Conclusions: Real-world data suggests growing and earlier use of GLP-1RA and SGLT-2i among BI users, and a growing proportion of PwT2D on BI-GLP-1RA combination treatment, in line with changing practice guidelines. Disclosure D. Schapiro: Employee; Eli Lilly and Company. A. Meeks: Employee; Eli Lilly and Company. D. Liu: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. F. Gelsey: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R. Juneja: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M. Perez-nieves: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A. Huang: None. Funding Eli Lilly and Company

183-LB: High Daily Doses of Insulin in Type 2 Diabetes—Predictors beyond Weight

In clinical practice, needing ≥ 200 units insulin/day is defined as severe insulin resistance. This study seeks to identify predictive characteristics of those with type 2 diabetes and severe insulin resistance (≥ 200 units insulin/day) vs. those using <100 units insulin/day. This retrospective cross-sectional study analyzed data for a six-month period gathered from a diabetes clinic electronic database. Compared were 59 patients using >200 units daily (high insulin users - HIU) vs. 59 patients using <100 units (low insulin users - LIU) . For the entire study group (n=118) , mean age was 57.7 ± 9.5 years, 66% were female and 52% Hispanic. Comparing groups, no differences seen in age, race, ethnicity, and A1c. Compared to LIU, HIU had more men (26 vs. 14, P=0.032) , higher BMI (41.8 ± 9.5 vs. 35.1 ± 6.6 kg/m2, p<0.001) , less physically active (42.5 (0.0, 120.0) vs. 140.0 (80.0, 180.0) min/week, p<0.001) , lower HDL (37.5 (32.0, 46.0) vs. 43.0 (37.0, 52.0) mg/dL, p=0.005) , higher insulin units/kg/day (2.3 ± 0.7 vs. 0.9 ± 0.3, p<0.001) , higher use of GLP1-RA medication (16 vs. 6, p=0.018) , higher incidence diabetic neuropathy (36 vs. 18, P<0.001) and co-morbid metabolic conditions like hypertension (58 vs. 50, p=0.024) , congestive heart failure (13 vs. 4, p=0.018) , metabolic liver disease (12 vs. 4, p=0.031) , and obstructive sleep apnea (18 v 7, p=0.013) . Per stepwise multivariate analysis, significant predictors of needing more insulin were being less active, lower HDL, co-morbid conditions like hypertension, neuropathy, obstructive sleep apnea, use of GLP1-RA and higher insulin/kg/day. Factors responsible for high insulin requirements go beyond weight alone as evidenced by higher insulin/kg/day in HIU. Insulin resistance may be exaggerated in the HIU by physical inactivity. Beta cell secretory dysfunction in HIU may also play a role as implied by their longer diabetes duration and higher rate of metabolic comorbid conditions. Disclosure J. Duron tabora: None. A. Amblee: n/a. B. Tahsin: n/a. L. Fogelfeld: Research Support; Lilly, Sanofi.

130-OR: The Association between High Out-of-Pocket Costs and Incidence of Treatment Intensification with an SGLT2 Inhibitor (SGLT2i) or GLP-1 Agonist (GLP-1a) in Patients with Type 2 Diabetes and Established Cardiovascular Disease: A Retrospective Cohort Study

The use of SGLT2i and GLP-1RA in patients with T2D remains low despite their known CV benefits. This may be due in part to high drug costs. We sought to assess the association between out-of-pocket (OOP) costs and the likelihood of initiating these two classes in patients with T2D and established CVD. We conducted a cohort study using claims data (Optum) , which included commercial and Medicare Advantage beneficiaries. Adults with T2D on metformin monotherapy between 12/5/17 and 12/31/were eligible. We excluded those:1) not continuously enrolled for ≥1 yr prior to their first metformin dispensing,2) with no evidence of established CVD, or3) whose OOP costs (defined as the sum of copays and deductibles for a 30-day supply) for SGLT2i or GLP-1RA could not be determined. We used Cox proportional hazards models adjusting for demographics, clinical characteristics, insurance plan, provider and laboratory characteristics to estimate hazard ratios (HR) of initiation across quartiles (Q) of OOP costs, with Q1 representing the lowest and Q4 the highest OOP costs. The cohort included 72,743 patients (mean[SD] age 72[9.4], 56% male) followed for a median of 914 days. Most (88%) were covered by a Medicare Advantage plan. The unadjusted incidence of initiating a SGLT2i (or GLP-1RA) was 2.8% (2.1%) in Q4 vs. 3.8% (2.8%) in Q1 of OOP costs. The median time to initiation of a SGLT2i/GLP-1RA was longer in Q4 (418/325 days) vs. Q1 (395/3 days) of OOP costs. In fully adjusted models, the HR for Q4 vs. Q1 of OOP costs was 0.79 (95%CI 0.70 to 0.90) for initiating a SGLT2i and 0.88 (95%CI: 0.77 to 1.01) for a GLP-1RA. In this national cohort of patients w/ T2D and established CVD, beneficiaries enrolled in plans in the highest quartile of OOP costs were significantly less likely to initiate a SGLT2i or GLP-1RA compared to those enrolled in plans in the lower quartile. Disclosure J.Luo: None. R.Feldman: None. S.D.Rothenberger: None. I.Hernandez: Consultant; Bristol-Myers Squibb Company, Pfizer Inc. M.T.Korytkowski: None. W.F.Gellad: None. Funding NIDDK (K23DK120956) NCATS (KL2TR001856)

934-P: Real-World Evidence of Glucose Lowering Drug Use, Glycemic Outcomes, and Severe Hypoglycemia in Hong Kong: Eighteen-Year Trends in 0.9 Million Adults with Diabetes

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c <7% in 2019. The 20-44 age group had the highest proportion with HbA1c ≥9% (22.1% in 2002 and 16.8% in 2019) compared with the ≥75 age-group (14.9% in 2002 and 5.5% in 2019) . SH rates declined between 2002-20 and further in 2010-2014. Between 2002-2019, metformin use increased steadily from 41.1% to 58.7%, sulfonylurea use decreased from 52.2% to 31.1% while insulin use remained static. Use of dipeptidyl-peptidase 4 inhibitors (DPP4i) experienced rapid growth between 2007-20equally in all age groups, with a slower rise between 2011-2019. DPP4i remains the most widely prescribed newer oral GLDs (14.3%) compared with sodium glucose co-transporter 2 inhibitors (SGLT2is) (4.2%) and glucagon like peptide-1 receptor agonists (GLP1-RAs) (0.6%) in 2019. Compared with over 75s, higher proportions of the 20-44 age-group were treated with SGLT2is (6.4% versus 1.7%) and GLP-1RAs (1.5% versus 0.1%) and thiazolidinediones (8.1% versus 3.4%) in 2019, irrespective of ASCVD status. Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

178-OR: Prescription Patterns of Cardiovascular and Kidney Protective Therapies among Patients with Type 2 Diabetes

Background: Recent guidelines recommend use of SGLT2i and/or GLP1-RA in persons with type 2 diabetes (T2D) and CVD or CKD, regardless of glycemic control. The degree of adoption of these recommendations thus far is unclear Methods: Among T2D patients receiving care within the VA Health Care System, we evaluated the prevalence and correlates of SGLT2i and GLP1-RA prescription during 20 and 2020. Logistic regression was used to examine associations of atherosclerotic CVD (ASCVD) , heart failure, and CKD (defined by lab values and/or administrative codes) as well as predicted risks of ASCVD and end-stage kidney disease (ESKD) , with prescription of SGLT2i and GLP1-RA Results: Of 1,319,500 adults with T2D, 10% and 7% were prescribed SGLT2is and GLP1-RAs, respectively. Prescription prevalence of SGLT2i and GLP1-RA were 13% and 9% in patients with established ASCVD; 14% and 11% in those with heart failure; and 11% and 10% in those with CKD. In adjusted models, patients with severe albuminuria were less likely to be prescribed an SGLT2i or a GLP1-RA versus non-albuminuric patients with CKD: aOR (95% CI) = 0.89 (0.87, 0.91) and 0.95 (0.93, 0.98) , respectively. In patients with 10-year ASCVD risk >20% versus those with risk <5%, ASCVD risk was inversely associated with prescription: SGLT2i OR=0.70 (0.60, 0.80) and GLP1-RA OR=0.60 (0.50, 0.70) . Patients with 5-year ESKD risk >5% were less likely to be prescribed an SGLT2i: OR=0.61 (0.57, 0.66) , versus those with ESKD risk <1% Conclusions: Among a national VA cohort of patients with T2D, prescription of SGLT2i and GLP1-RA was pervasively low across conditions for which they are currently indicated to lower the risk of CVD and CKD progression. Furthermore, we observed a “risk-treatment paradox”, where patients with higher risk of adverse outcomes were less likely to receive these therapies. Intensive implementation efforts are needed to prioritize prescription of these medications to patients who would derive the largest benefit. Disclosure J.A. Lamprea Montealegre: Research Support; Bayer AG. E. Madden: None. S. Tummalapalli: Consultant; Bayer AG. Research Support; Scanwell Health. C. Chu: Research Support; Bayer AG. Y. Du: Employee; Bayer AG. Stock/Shareholder; Bayer AG. R. Singh: None. S. Kong: Employee; Bayer AG. D.S. Tuot: None. C. Peralta: Employee; Cricket Health, Inc. Research Support; American Heart Association, National Institutes of Health. M.G. Shlipak: Advisory Panel; TAI Diagnostics. Consultant; Cricket Health, Intercept Pharmaceuticals, Inc. Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH. M. Estrella: Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH.

Type 2 diabetes medication and HbA1c levels in North Karelia Finland, 2013-2019.

AimsTo analyse the prevalence of prescribed medications among people with type 2 diabetes, their relationship to HbA1c levels and transitions between medications.MethodsThe data included all 18‐ to 85‐year‐old adults with type 2 diabetes (identified from the electronic health records), who lived in North Karelia, Finland, between 2013 and 2019. Type 2 diabetes medication was defined based on prescriptions. Logistic and linear regressions with generalized estimating equations were used to assess the differences between years.ResultsMetformin as a monotherapy was the most used medication (33%–35%) with the largest percentage of those in good glycaemic control. After metformin, the most used medications were long‐acting and short‐acting insulin and gliptin (16%–24% per group). In insulin groups, there were the smallest percentage of people in good glycaemic control. The use of SGLT2‐i increased most during the follow‐up (from 1.6% to 11%), but at the same time the percentage of those meeting the target HbA1c level decreased the most (from 83% to 53%). The use of GLP‐1 RA and other medications were under 3.5%. SGLT2‐i and insulin were the most stable medication groups. The most common transitions were from SGLT2‐i to long‐acting insulin and between insulin groups.ConclusionsThe sequencing of prescribing additional type 2 diabetes medication or replacing current medication with new ones seems to occur according to guidelines. However, more attention should be paid to the intensification of treatment and the possibilities for new treatment choices in the management of T2D taking into account the persons’ characteristics.

Effect of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese adults without diabetes: A meta-analysis of placebo-controlled randomized trials.

Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the risk of any cardiovascular event in adults with overweight or obesity and without diabetes. We conducted a random-effects meta-analysis of placebo-controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430 patients were included, of which 7702 (67%) were submitted to treatment with GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%) and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascular event (RR=0.81, CI 0.70-0.92; p=.001). In overweight or obese adults without diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our findings support the use of GLP-1 RA for reducing the cardiovascular risk of these patients.

Global use of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Results from DISCOVER

BackgroundDespite strong evidence of benefit, uptake of newer glucose-lowering medications that reduce cardiovascular risk has been low. We sought to examine global trends and predictors of use of SGLT2i and GLP-1 RA in patients with type 2 diabetes.MethodsDISCOVER is a global, prospective, observational study of patients with diabetes enrolled from 2014–16 at initiation of second-line glucose-lowering therapy and followed for 3 years. We used hierarchical logistic regression to examine factors associated with use of either an SGLT2i or GLP-1 RA at last follow-up and to assess country-level variability.ResultsAmong 14,576 patients from 37 countries, 1579 (10.8%) were started on an SGLT2i (1275; 8.7%) or GLP-1 RA (318; 2.2%) at enrollment, increasing to 16.1% at end of follow-up, with large variability across countries (range 0–62.7%). Use was highest in patients treated by cardiologists (26.1%) versus primary care physicians (10.4%), endocrinologists (16.9%), and other specialists (22.0%; p < 0.001). Coronary artery disease (OR 1.29, 95% CI 1.08–1.54) was associated with greater use of SGLT2i or GLP-1 RA while peripheral artery disease (OR 0.73, 95% CI 0.54–1.00) and chronic kidney disease (OR 0.73, 95% CI 0.58–0.94) were associated with lower use (OR 0.73, 95% CI 0.54–1.00). The country-level median odds ratio was 3.48, indicating a very large amount of variability in the use of SGLT2i or GLP-1 RA independent of patient demographic and clinical factors.ConclusionsGlobal use of glucose-lowering medications with established cardiovascular benefits has increased over time but remains suboptimal, particularly in sub-groups most likely to benefit. Substantial country-level variability exists independent of patient factors, suggesting structural barriers may limit more widespread use of these medications.

IDF21-0203 A1C Target Attainment Without Hypoglycemia According to BMI: Insulin Glargine 300 U/mL vs 1st-Generation Basal Insulin

Background: High BMI is associated with insulin resistance and greater basal insulin (BI) requirements, which can lead to increased risk of hypoglycemia. The real-life, pragmatic, randomized ACHIEVE Control study (NCT02451137) demonstrated that among insulin-naive adults with T2D ≥1 year and A1C 8–11%, those who received the 2nd-generation BI analog glargine 300 U/mL (Gla-300) were significantly more likely to achieve individualized A1C targets (<8% for participants ≥65 years or with defined comorbidities; <7% for all others) without documented symptomatic (≤70 mg/dL) and/or severe hypoglycemia versus first-generation BI analogs (insulin glargine 100 U/mL; insulin detemir) at 6 months, with the trend continuing at 12 months. Aim: This post-hoc analysis of ACHIEVE Control explored the correlation between A1C target attainment without hypoglycemia with daily insulin dose according to BMI. Method: Participants were categorized according to baseline BMI (<30, 30–<35, 35–<40, ≥40 kg/m2). Proportions of participants achieving individualized A1C targets without documented symptomatic (≤70 and <54 mg/dL) and/or severe hypoglycemia; mean daily insulin doses at 6 and 12 months were estimated. Results: The <30 kg/m2 BMI group comprised individuals who were predominantly male (61 vs 42–58%), were older (61.7 vs 55.1–59.7 years), and had longer duration of T2D (12.6 vs 9.8–11.2 years) versus those with higher BMIs. Mean A1C was 9.1–9.2% across all BMI subgroups. Background medication use was generally well balanced, except for higher GLP-1 RA use as BMI increased. The proportion of individuals with the more stringent A1C goal of <7% increased as BMI increased, likely related to their younger age. Insulin dose at 12 months (U/kg/day) was similar across all BMI categories (range: 0.351–0.395). At both 6 and 12 months, a numerically higher proportion of participants who received Gla-300 versus 1st-generation BIs achieved their individualized A1C target without documented symptomatic (at both ≤70mg/dL and <54 mg/dL) or severe hypoglycemia (except for the ≥40 kg/m2 group at 6 months) (Table). Discussion: The results of this post-hoc analysis were consistent with those of the primary endpoint of the overall ACHIEVE Control study. The trend for benefit of Gla-300 versus 1st-generation BI for achievement of individualized A1C target without documented symptomatic and/or severe hypoglycemia at 12 months was consistent regardless of BMI.

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.ObjectiveTo evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.Data SourcesMEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.Study SelectionRandomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.Data Extraction and SynthesisTwo reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.Main Outcomes and MeasuresThe primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.ResultsA total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).Conclusions and RelevanceThis systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.Trial RegistrationPROSPERO Identifier: CRD42021271599

Correlates of Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes Mellitus (from the Department of Veterans Affairs)

This study used data from the Veterans Affairs administrative and clinical dataset to evaluate determinants of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among patients with concomitant atherosclerotic cardiovascular disease and diabetes mellitus and an antecedent primary care provider visit. The prevalence of GLP-1 RA use was 8.0%. In multivariable-adjusted models, White race, hypertension, obesity, higher hemoglobin A1c, ischemic heart disease, chronic kidney disease, a higher number of primary care provider visits, and previous cardiology or endocrinology visits were directly associated with GLP-1 RA use. Older age, having a physician primary care provider, and receiving care at a teaching facility were inversely associated with GLP-1 RA use. Our data can help inform targeted interventions to promote equitable access to GLP-1 RA and incentivize the adoption of these disease-modifying agents in high-risk patient populations.

Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.Graphical

Low Use of Guideline-recommended Cardiorenal Protective Antihyperglycemic Agents in Primary Care: A Cross-sectional Study of Adults With Type 2 Diabetes

ObjectivesGlucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown cardiorenal benefits independent of their glucose-lowering effects among persons living with type 2 diabetes mellitus (T2DM). In this study, we describe the proportion of persons with T2DM eligible to receive and currently receiving these agents based on their risk criteria for cardiorenal events. MethodsThis study was a cross-sectional analysis of primary care electronic medical records, in southern Alberta, of persons with T2DM who had at least 1 encounter with their primary care provider between December 31, 2018, to December 31, 2020. A descriptive and multivariate logistic regression analysis was conducted to examine clinical and demographic determinants of being prescribed one of the new treatments. ResultsOur study sample included 11,939 persons living with T2DM, among whom 66.3% had a cardiorenal indication for SGLT2i or GLP-1 RA use. In the secondary and primary prevention subsamples, 19.4% and 16.6% of persons were prescribed SGLT2i or GLP-1 RA, respectively, compared with 20.0% of those with no specific cardiorenal indication. Several person-level characteristics, such as age (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.96 to 0.97), male sex (OR, 1.37; 95% CI, 1.21 to 1.55) and glycated hemoglobin (OR, 1.29; 95% CI, 1.24 to 1.34), were associated with being prescribed SGLT2i or GLP-1 RA. ConclusionsLow rates of SGLT2i or GLP-1 RA use and minimal differences between high-risk and no cardiorenal indication subsamples suggest the presence of barriers to prescribing these medications in a primary care setting. Action to highlight the indications for, and improve access to agents with, cardiorenal benefits will be required to achieve better outcomes for people with T2DM in primary care.

Utilization Rates of SGLT2 Inhibitors and GLP-1 Receptor Agonists and Their Facility-Level Variation Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes: Insights From the Department of Veterans Affairs.

There is mounting evidence regarding the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) among patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM). There is paucity of data assessing real-world practice patterns for these drug classes. We aimed to assess utilization rates of these drug classes and facility-level variation in their use. We used the nationwide Veterans Affairs (VA) health care system data set from 1 January 2020 to 31 December 2020 and included patients with established ASCVD and T2DM. Among these patients, we assessed the use of SGLT2i and GLP-1 RA and the facility-level variation in their use. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of SGLT2i and GLP-1 RA in patients with ASCVD and T2DM. Among 537,980 patients with ASCVD and T2DM across 130 VA facilities, 11.2% of patients received an SGLT2i while 8.0% of patients received a GLP-1 RA. Patients receiving these cardioprotective glucose-lowering drug classes were on average younger and had a higher proportion of non-Hispanic Whites. Overall, median (10th-90th percentile) facility-level rates were 14.92% (9.31-22.50) for SGLT2i and 10.88% (4.44-17.07) for GLP-1 RA. There was significant facility-level variation among SGLT2i use-MRRunadjusted: 1.41 (95% CI 1.35-1.47) and MRRadjusted: 1.55 (95% CI 1.46 -1.63). Similar facility-level variation was observed for use of GLP-1 RA-MRRunadjusted: 1.34 (95% CI 1.29-1.38) and MRRadjusted: 1.78 (95% CI 1.65-1.90). Overall utilization rates of SGLT2i and GLP-1 RA among eligible patients are low, with significantly higher residual facility-level variation in the use of these drug classes. Our results suggest opportunities to optimize their use to prevent future adverse cardiovascular events among these patients.

Trends in the Degree of Control and Treatment of Cardiovascular Risk Factors in People With Type 2 Diabetes in a Primary Care Setting in Catalonia During 2007-2018.

ObjectiveTo assess the trends in cardiovascular risk factor control and drug therapy from 2007 to 2018 in subjects with type 2 diabetes mellitus (T2DM).Materials and MethodsCross-sectional analysis using yearly clinical data and treatment obtained from the SIDIAP database. Patients aged ≥18 years with a diagnosis of T2DM seen in primary care in Catalonia, Spain. ResultsThe number of T2DM patients increased from 299,855 in 2007 to 394,266 in 2018. We also found an increasing prevalence of cardiovascular disease, heart failure, and chronic kidney disease (from 18.4 to 24.4%, from 4.5 to 7.3%, and from 20.2 to 31.3%, respectively). The achievement of glycemic targets (HbA1c<7%) scarcely changed (54.9% to 55.9%). Major improvements were seen in blood pressure (≤140/90 mmHg: from 55% to 71.8%), and in lipid control (low-density lipoprotein cholesterol <100 mg/dl: 33.4% to 48.4%), especially in people with established cardiovascular disease (48.8 to 69.7%). Simultaneous achievement of all three targets improved from 12.5% to 20.1% in the overall population and from 24.5% to 32.2% in those with cardiovascular disease but plateaued after 2013. There was an increase in the percentage of patients treated with any antidiabetic drug (70.1% to 81.0%), especially metformin (47.7% to 67.7%), and DPP4i (0 to 22.6%). The use of SGLT-2 and GLP-1ra increased over the years, but remained very low in 2018 (5.5% and 2.1% of subjects, respectively). There were also relevant increases in the use of statins (38.0% to 49.2%), renin-angiotensin system (RAS) drugs (52.5% to 57.2%), and beta-blockers (14.3% to 22.7%).ConclusionsDuring the 2007-2018 period, relevant improvements in blood pressure and lipid control occurred, especially in people with cardiovascular disease. Despite the increase in the use of antidiabetic and cardiovascular drugs, the proportion of patients in which the three objectives were simultaneously achieved is still insufficient and plateaued after 2013. The use of antidiabetic drugs with demonstrated cardio renal benefits (SGLT-2 and GLP-1ra) increased over the years, but their use remained quite low.

Racial, Ethnic, and Socioeconomic Inequities in Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Diabetes in the US

Randomized clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause significant weight loss and reduce cardiovascular events in patients with type 2 diabetes (T2D). Black patients have a disproportionate burden of obesity and cardiovascular disease and have a higher rate of cardiovascular-related mortality. Racial and ethnic disparities in health outcomes are largely attributable to the pervasiveness of structural racism, and patients who are marginalized by racism have less access to novel therapeutics. To evaluate GLP-1 RA uptake among a commercially insured population of patients with T2D; identify associations of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use; and specifically examine its use among the subgroup of patients with atherosclerotic cardiovascular disease (ASCVD) because of the known benefit of GLP-1 RA use for this population. This was a retrospective cohort analysis using data from OptumInsight Clinformatics Data Mart of commercially insured adult patients with T2D (with or without ASCVD) in the US. Data from October 1, 2015, to June 31, 2019, were included, and the analyses were performed in July 2020. We estimated multivariable logistic regression models to identify the association of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use. A prescription for a GLP-1 RA. Of the 1 180 260 patients with T2D (median [IQR] age, 69 [59-76] years; 50.3% female; 57.7% White), 90 934 (7.7%) were treated with GLP-1 RA during the study period. From 2015 to 2019, the percentage of T2D patients treated with an GLP-1 RA increased from 3.2% to 10.7%. Among patients with T2D and ASCVD, use also increased but remained low (2.8%-9.4%). In multivariable analyses, lower rates of GLP-1 RA use were found among Asian (aOR, 0.59; 95% CI, 0.56-0.62), Black (adjusted odds ratio [aOR] 0.81; 95% CI, 0.79-0.83), and Hispanic (aOR, 0.91; 95% CI, 0.88-0.93) patients with T2D. Female sex (aOR, 1.22; 95% CI, 1.20-1.24) and higher zip code-linked median household incomes (>$100 000 [OR, 1.13; 95% CI, 1.11-1.16] and $50 000-$99 999 [OR, 1.07; 95% CI, 1.05-1.09] vs <$50 000) were associated with higher GLP-1 RA use. These results were similar to those found among patients with ASCVD. In this cohort study of US patients with T2D, GLP-1 RA use increased, but remained low overall for treatment of T2D, particularly among patients with ASCVD who are likely to derive the most benefit. Asian, Black, and Hispanic patients and those with low income were less likely to receive treatment with a GLP-1 RA. Strategies to lower barriers to GLP-1 RA use, such as lower cost, are needed to prevent the widening of well-documented inequities in cardiovascular disease outcomes in the US.

Abstract 14383: Medical Therapy Before, During, and After Hospitalization in Medicare Beneficiaries With Heart Failure and Diabetes: The Get With the Guidelines - Heart Failure Registry

Introduction: Patients with heart failure with reduced ejection fraction (HFrEF) and diabetes mellitus (DM) are at risk for worsening HF events, yet little is known about therapeutic changes surrounding hospitalization. We aimed to characterize use of medical therapies before, during, and after hospitalization for HF. Methods: We identified Medicare beneficiaries in the GWTG-HF registry with HFrEF and DM who were hospitalized between July 2016 and September 2017 and had Part D prescription coverage for ≥6 months before and ≥3 months after hospital discharge. Medication fills for evidence-based HFrEF and antihyperglycemic therapies were assessed at 6 and 3 months before hospitalization, at hospital discharge, and 3 months post-discharge. Results: Among 3,272 Medicare beneficiaries with HFrEF and DM, mean age was 77±7y, 41% were women, and 15% were Black. Overall, 92%, 56%, 28%, and 6% were prescribed β-blocker, ACEi/ARB, MRA, and ARNI at discharge. Rates of all therapies were higher at discharge than immediately prior to hospitalization, though rates of β-blocker and ACEi/ARB use declined 3-months post-discharge. ‘Triple therapy’ (ACEI/ARB/ARNI+β-blocker+MRA) was prescribed in 9% prior to hospitalization and 20-21% at discharge and early-post-discharge. After hospitalization, insulin was prescribed most frequently (35%), followed by metformin (21%), sulfonylureas (19%), and DPP4i (11%), while GLP-1RA (2%) and SGLT2i (0.5%) use was infrequent. Modest changes in antihyperglycemic therapies were observed pre- vs. post-hospitalization, including an increase in insulin from 32% to 35% and decrease in metformin from 26% to 21% and SGLT2i from 0.8% to 0.5%. Conclusions: Despite modest improvements in use of evidence-based therapies for HFrEF during and shortly after hospitalization for HF, only 1 out of 5 patients are treated with comprehensive medical therapy. Early adoption in 2016-2017 of SGLT2i was low in a high-risk population with comorbid HFrEF and DM.