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Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics.In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of propensity matching based on age, race, sex, coronary disease, HF, diabetes duration, and number of antidiabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary end points. We identified 1,426 users of GLP-1 agents and 2,798 control subjects. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, number of antidiabetic medications, and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.34-0.77; P = .002), all-cause hospitalization (aHR 0.54, 95% CI 0.38-0.74; P = .001), and death (aHR 0.31, 95% CI 0.18-0.53; P = .001).GLP-1 agents may reduce the risk of HF events in diabetics.

SUBMITTER: Velez M

PROVIDER: S-EPMC4276467 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

Velez Mauricio M Peterson Edward L EL Wells Karen K Swadia Tanmay T Sabbah Hani N HN Williams L Keoki LK Lanfear David E DE

Journal of cardiac failure 20141028 1

<h4>Background</h4>Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics.<h4>Methods and results</h4>In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of pr ...[more]

PMID: 25451709

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Project description:ImportanceUnderstanding cardiovascular outcomes of initiating second-line antidiabetic medications (ADMs) may help inform treatment decisions after metformin alone is not sufficient or not tolerated. To date, no studies have compared the cardiovascular effects of all major second-line ADMs during this early decision point in the pharmacologic management of type 2 diabetes.ObjectiveTo examine the association of second-line ADM classes with major adverse cardiovascular events.Design, setting, and participantsRetrospective cohort study among 132 737 insured adults with type 2 diabetes who started therapy with a second-line ADM after taking either metformin alone or no prior ADM. This study used 2011-2015 US nationwide administrative claims data. Data analysis was performed from January 2017 to October 2018.ExposuresDipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones (TZDs), basal insulin, and sulfonylureas or meglitinides (both referred to as sulfonylureas hereafter). The DPP-4 inhibitors served as the comparison group in all analyses.Main outcomes and measuresThe primary outcome was time to first cardiovascular event after starting the second-line ADM. This composite outcome was based on hospitalization for the following cardiovascular conditions: congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease.ResultsAmong 132 737 insured adult patients with type 2 diabetes (men, 55%; aged 45-64 years, 58%; white, 63%), there were 3480 incident cardiovascular events during 169 384 person-years of follow-up. Patients were censored after the first cardiovascular event, discontinuation of insurance coverage, transition from International Classification of Diseases, Ninth Revision (ICD-9) to end of ICD-9 coding, or 2 years of follow-up. After adjusting for patient, prescriber, and health plan characteristics, the risk of composite cardiovascular events after starting GLP-1 receptor agonists was lower than DPP-4 inhibitors (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96), but this finding was not significant in all sensitivity analyses. Cardiovascular event rates after starting treatment with SGLT-2 inhibitors (HR, 0.81; 95% CI, 0.57-1.53) and TZDs (HR, 0.92; 95% CI, 0.76-1.11) were not statistically different from DPP-4 inhibitors. The comparative risk of cardiovascular events was higher after starting treatment with sulfonylureas (HR, 1.36; 95% CI, 1.23-1.49) or basal insulin (HR, 2.03; 95% CI, 1.81-2.27) than DPP-4 inhibitors.Conclusions and relevanceAmong insured adult patients with type 2 diabetes initiating second-line ADM therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar. Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer ADM classes. Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.

Project description:Background Mechanistic insights of glucagon-like peptide-1 receptor agonists remain incompletely identified, despite the efficacy in heart failure observed in clinical trials. Here, we evaluated the effects of dulaglutide on heart complications and illuminated its underlying mechanism. Methods and Results We used mice with high-fat diet (HFD)/streptozotocin-induced type 2 diabetes to investigate the effects of dulaglutide upon diabetic cardiac dysfunction. After the onset of diabetes, control and diabetic mice were injected subcutaneously with either dulaglutide (type 2 diabetes-dulaglutide and control-dulaglutide groups) or vehicle (type 2 diabetes-vehicle and control-vehicle groups) for 8 weeks. Subsequently, heart characteristics, cardiometabolic profile and mitochondrial morphology and function were evaluated. Also, we analyzed the effects of dulaglutide on neonatal rat ventricular myocytes treated with high glucose plus palmitic acid. In addition, wild type and AMP-activated protein kinase α2 mutant mice were used to evaluate the underlying mechanism. In type 2 diabetes mouse model, dulaglutide ameliorated insulin resistance, improved glucose tolerance, reduced hyperlipidemia, and promoted fatty acid use in the myocardium. Dulaglutide treatment functionally attenuated cardiac remodeling and dysfunction and promoted metabolic reprogramming in diabetic mice. Furthermore, dulaglutide improved mitochondria fragmentation in myocytes, and simultaneously reinstated mitochondrial morphology and function in diabetic hearts. We also found that dulaglutide preserved AMP-activated protein kinase α2-dependent mitochondrial homeostasis, and the protective effects of dulaglutide on diabetic heart was almost abated by AMP-activated protein kinase α2 knockout. Conclusions Dulaglutide prevents diabetic heart failure and favorably affects myocardial metabolic remodeling by impeding mitochondria fragmentation, and we suggest a potential strategy to develop a long-term activation of glucagon-like peptide-1 receptor-based therapy to treat diabetes associated cardiovascular complications.

Project description:ObjectiveTo review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes.DesignSystematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes.Data sourcesElectronic databases, manual reference search, and contact with investigators.Review methodsTwo reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate.ResultsEight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies.ConclusionMetformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies.

Project description:ObjectivesThis study sought to describe the patterns of heart failure (HF)-exacerbating medications used among older adults hospitalized for HF and to examine determinants of HF-exacerbating medication use.BackgroundHF-exacerbating medications can potentially contribute to adverse outcomes and could represent an important target for future strategies to improve post-hospitalization outcomes.MethodsMedicare beneficiaries ≥65 years of age with an adjudicated HF hospitalization between 2003 and 2014 were derived from the geographically diverse REGARDS (Reasons for Geographic and Racial Difference in Stroke) cohort study. Major HF-exacerbating medications, defined as those listed on the 2016 American Heart Association Scientific Statement listing medications that can precipitate or induce HF, were examined. Patterns of prescribing medications at hospital admission and at discharge were examined, as well as changes that occurred between admission and discharge; and a multivariable logistic regression analysis was conducted to identify determinants of harmful prescribing practices following HF hospitalization (defined as either the continuation of an HF-exacerbating medications or an increase in the number of HF-exacerbating medications between hospital admission and discharge).ResultsAmong 558 unique individuals, 18% experienced a decrease in the number of HF-exacerbating medications between admission and discharge, 19% remained at the same number, and 12% experienced an increase. Multivariable logistic regression analysis revealed that diabetes (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.18 to 2.75]) and small hospital size (OR: 1.93; 95% CI: 1.18 to 3.16) were the strongest, independently associated determinants of harmful prescribing practices.ConclusionsHF-exacerbating medication regimens are often continued or started following an HF hospitalization. These findings highlight an ongoing need to develop strategies to improve safe prescribing practices in this vulnerable population.

Project description:The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes.We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence.We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI) 0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and a case-control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42).The current evidence suggests that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure among patients with type 2 diabetes.

Project description:Background & aimsThe study sought to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes.MethodsThis population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis, in a commercial healthcare database (IBM MarketScan). We constructed 3 pairwise, 1:1 propensity score (PS)-matched cohorts of adults initiating GLP-1RAs or a comparator medication (ie, DPP-4 inhibitors [2006-2020], sulfonylurea [2005-2020], or SGLT-2 inhibitors [2013-2020]). Patients were followed in an as-treated approach for decompensation events (ie, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >90 baseline characteristics.ResultsOver 132 days of median follow-up (interquartile range, 73-290 days), PS-matched rates of any decompensation were significantly lower among GLP-1RA initiators, versus DPP-4 inhibitor initiators (105.2 vs 144.0 per 1000 person-years [PY]; HR, 0.68; 95% CI, 0.53-0.88; n = 1431 pairs), and versus sulfonylureas (97.3 vs 144.0 per 1000 PY; HR, 0.64; 95% CI, 0.48-0.84; n = 1246 pairs). Similar, inverse associations were found for individual decompensation events, including ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome (HR, 0.66; 95% CI, 0.45-0.97; and HR, 0.66; 95% CI, 0.46-0.94, respectively); esophageal variceal hemorrhage (HR, 0.62 [95% CI, 0.41-0.92; and HR, 0.59; 95% CI, 0.37-0.92, respectively); and hepatic encephalopathy (HR, 0.76; 95% CI, 0.55-1.06; and HR, 0.60; 95% CI, 0.39-0.92, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar when GLP-1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR, 0.89; 95% CI, 0.62-1.28).ConclusionsAmong cirrhotic patients with type 2 diabetes, we find high rates of decompensation, consistent with previous reports; these rates were substantially lower among GLP-1RA initiators compared with DPP-4 inhibitors or sulfonylureas.

Dataset Information

Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

Publications

Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

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