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. 2023 Sep 17;15(9):e45421. doi: 10.7759/cureus.45421

Safety and Efficacy of Liraglutide on Cardiovascular Outcomes in Patients With Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials

Hema Srikanth Vemulapalli 1, Jaahnavi Vajje 2, Wajeeh Rehman 3,✉, Ghazala S Virk 4, Krushi Shah 5, Sandipkumar S Chaudhari 6,7, Irfan-ud-din Mian 8, Faraz Saleem 9,10
Editors: Alexander Muacevic, John R Adler
PMCID: PMC10581595  PMID: 37854744

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder, with type 2 diabetes (T2DM) significantly impacting the cardiovascular (CV) system. Our comprehensive study on the cardiovascular effects of liraglutide, conducted concurrently with the formulation of diabetes treatment guidelines, aims to provide healthcare providers and patients with reassurance regarding the safety and effectiveness of liraglutide.

From the beginning until August 20, 2023, we conducted searches in databases including PubMed, Web of Science, Embase, Cochrane Library, Scopus, and Google Scholar. These searches aimed to identify studies comparing liraglutide to control in terms of symptom resolution among patients with T2DM. For all relevant outcomes, we calculated risk ratios along with their corresponding 95% confidence intervals.

Thirteen randomized controlled trials (RCTs) were included in this analysis. The results demonstrated a significant reduction in the risk of major adverse cardiovascular events (MACE), myocardial infarction, CV mortality, and all-cause mortality. No significant difference was found between the liraglutide and control groups for the outcome of stroke. However, sensitivity analysis revealed a significant reduction in the risk of stroke among patients taking liraglutide. Our comprehensive meta-analysis strongly supports the use of liraglutide for managing cardiovascular disease (CVD) due to its established safety and effectiveness. Further RCTs and meta-analyses are needed to more thoroughly evaluate liraglutide's therapeutic potential, with the aim of enhancing the quality of life for those with CVD.

Keywords: randomized controlled trials, meta-analysis, diabetes mellitus, patients, cardiovascular outcomes, liraglutide, efficacy, safety

Introduction and background

Diabetes mellitus (DM), as defined by the World Health Organization (WHO), is a chronic metabolic disorder. It is characterized by elevated levels of blood glucose, gradually leading to detrimental effects on various organs such as the heart, eyes, vasculature, nerves, and kidneys. More than 90% of DM cases are classified as type 2 diabetes mellitus (T2DM), characterized by insufficient insulin production by pancreatic β-cells, inadequate insulin secretion, and tissue resistance to insulin [1,2]. The prevalence of diabetes in individuals aged ≥20 years is 9.5%, resulting in 21.8 million diagnosed cases among noninstitutionalized United States (U.S.) civilians [3].

At the clinical level, T2DM is significantly correlated with consequences affecting both the macrovascular and microvascular systems. These encompass nephropathy, retinopathy, neuropathy, peripheral arterial disease (PAD), cerebrovascular disease, and ischemic heart disease (IHD) [4]. DM triples cardiovascular (CV) mortality risk and doubles total mortality risk [5,6], but concerns over the potential CV effects of certain glucose-lowering treatments remain to be definitively confirmed [7,8]. Thus, the U.S. Food and Drug Administration (FDA) revised industry rules to mandate CV risk assessment for new diabetic drugs through rigorous randomized controlled trials (RCTs) [7,8]. Concentrating on the complex diabetes-cardiovascular mortality relationship is essential due to increased mortality risk. Our investigation aims to uncover therapeutic interventions targeting mortality-contributing factors [7,8].

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous hormones responsible for the incretin effect [5,8,9]. GLP-1 is crucial for beta cell formation, inducing insulin production, and enhancing insulin gene expression, thus significantly reducing blood glucose levels and modifying T2DM's course and progression [5,8,9]. GLP-1-based medications' glucose-lowering and weight-reducing benefits impact CV factors, with recent research suggesting additional CV benefits unrelated to glucose reduction. Experimental models demonstrate diverse CV effects of GLP-1, including heart rate modulation, vascular tone, myocardial contractility, blood pressure regulation, and protection against ischemia-reperfusion injury [9].

Liraglutide, an extended version of GLP-1, shares a 97% amino acid sequence similarity with human GLP-1. Scientific evidence supports Liraglutide's efficacy in reducing glucose levels, as evidenced by trials showing slight declines in blood pressure and body weight [10-12]. The surge in liraglutide CV trials for type 2 diabetes prompted our FDA-protocol-aligned meta-analysis. We conclude that targeted diabetic therapy will revolutionize care. Our comprehensive CV effect study of liraglutide, aligned with developing diabetes treatment guidelines, aims to reassure healthcare providers and patients. This investigation aims to determine liraglutide's potential influence on major CV events in T2DM patients, underscoring its critical role as an intervention [10-12].

Review

Methods

The current meta-analysis and systematic review adhere to a predetermined protocol in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis is based on previously documented investigations, so ethical approval and participant consent were deemed unnecessary [13].

Search Strategy and Selection Criteria

We conducted a comprehensive systematic search of Google Scholar, the Cochrane Library, PubMed, the Web of Science, Embase, and Scopus from their inception until August 20, 2023. The study keywords included "type 2 diabetes," "liraglutide," and "cardiovascular," along with the Boolean operators AND and OR. Detailed search strategy information is available in Appendix A.

The literature search, data extraction, and quality assessment were independently performed by two writers. Additional searches were conducted through references cited in the included studies to ensure comprehensive coverage. In cases where original research lacked important data, authors were contacted for clarification. Two authors independently screened and assessed study eligibility. Inclusion criteria were: (1) RCTs investigating liraglutide's efficacy and safety on cardiovascular outcomes in T2DM patients with and without pre-existing cardiovascular disease (CVD); (2) adult T2DM patients with > 12 weeks of disease duration and 7.0% glycated hemoglobin. The analysis involved comparing liraglutide-treated patients to those receiving alternative anti-diabetic treatment or a placebo. Studies with redundant/insufficient data for effect estimation and those involving non-diabetic or type 1 diabetic patients were excluded.

Data Extraction and Outcomes

Data extraction, conducted independently by two investigators, ensured the result's credibility. Disagreements were resolved through consensus, and a third reviewer was consulted if further clarification was needed. Data from studies meeting inclusion criteria were collected using a standard method. The information included the primary author's name, publication year, research country, intervention details, event and control quantities, baseline patient characteristics (age, gender, race, diabetes duration, HbA1c levels, body mass index), and occurrence of cardiovascular events.

The primary outcome assessed liraglutide's impact compared to alternative antidiabetic treatments or placebo on major adverse cardiovascular events (MACE). These events included nonfatal acute myocardial infarction (AMI), cardiovascular death, stroke, acute coronary syndromes, heart failure, or both. Secondary outcomes included myocardial infarction, stroke, all-cause mortality, and CV-related mortality.

Quality Assessment and Statistical Analysis

The quality assessment of clinical trials was independently conducted by two researchers using the Risk of Bias Tool 2 (ROB 2.0) (Appendix B1) [14]. This tool is widely employed for clinical trial quality evaluation. Statistical analysis and forest plot generation were performed using Review Manager 5.4. Forest plots using a random effects model determined the pooled effect size. A funnel plot assessed publication bias (Appendix B2). A p-value of <0.05 was considered statistically significant.

Results

Literature Search Results

The comprehensive screening process is depicted in Figure 1 through the PRISMA flow chart. After duplicate removal and filtering, 13 papers were evaluated.

Figure 1. PRISMA flow diagram.

Figure 1

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Study Characteristics

Table 1 outlines study characteristics and initial participant demographics. The study included 50,751 participants with an average age of 59.4 years. Participants' mean BMI was 31.4, and all included patients had HbA1c levels exceeding 8.

Table 1. Baseline characteristics of the included studies.

          Mean
Author (year) Study description Liragitude Comparators Sex (M/F) Age (years) BMI (kg/m2) Diabetes duration HbA1c (%)
Marre et al. [15] Add-on to glimepiride 695 114 (placebo) 405/404 56 30 7 8.4
Nauck et al. [16] Add-on to metformin 724 232 (rosiglitazone) 121 (placebo) 462/465 495/350 56 57 29.8 31.2 7 7 8.4 8.4
Russell-Jones et al. [17] Add-on to metformin and glimepiride 232 242 (glimepiride) 115 (placebo) 560/406 189/158 57 57 31.2 30.3 7 9 8.4 8.3
Zinman et al. [18] Add-on to metformin and rosiglitazone 355 234 (glargine) 175 (placebo) 273/193 302/228 57 55 30.8 33.7 9 9 8.3 8.5
Pratley et al. [19] Monotherapy 446 219 (Sitagliptin) 352/313 55 32.8 6 8.4
Seino et al. [20] Monotherapy 268 132 (Glibenclamide) 268/132 58 24.4 8 8.8
Garber et al. [21] Monotherapy 498 248 (glimepiride) 371/375 53 33 5 8.3
Marso et al. [22] Monotherapy 4668 4672 (placebo) 6003/3337 64.3 32.5 12.7 8.7
Verma et al. [23] Monotherapy 4668 4672 (placebo) 6003/3337 64.4 32.6 12.8 8.7
Mann et al. [24] Monotherapy 1116 1042 (placebo) 1322/836 67.3 32.7 15.2 8.7
Nauck et al. [25] Monotherapy 4668 4672 (placebo) 6003/3337 64.3 n/a 12.9 8.7
Gilbert et al. [26] Monotherapy 3053 3130 (placebo) 3935/2248 65.8 32.4 13.2 8.7
Marso et al. [27] Monotherapy 4668 4672 (placebo) 6003/3337 64.2 33.1 12.4 8.7
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Results of Meta-Analysis

MACE: Pooling results from 11 studies assessed MACE outcomes. Liraglutide significantly reduced MACE risk compared to the control group (RR=0.89; 95% CI: 0.84-0.93; P<0.00001; I2=0%) (Figure 2).

Figure 2. Comparison of MACE.

Figure 2

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MACE: major cardiovascular events [15-19,21-27]

Myocardial infarction: Twelve studies were combined to assess myocardial infarction occurrence. Liraglutide significantly reduced myocardial infarction incidence compared to the control group (RR=0.88; 95% CI: 0.78-1.00; P=0.04; I2=39%) (Figure 3). Sensitivity analysis confirmed consistent results with reduced heterogeneity (RR=0.83; 95% CI: 0.74-0.92; P=0.0005; I2=0%) (Appendix C).

Figure 3. Comparison of myocardial infarction.

Figure 3

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[15,17-27]

Stroke: Six studies evaluated stroke outcomes. No significant difference between liraglutide and control groups was found (RR=0.85; 95% CI: 0.73-1.00; P=0.05; I2=44%) (Figure 4). Sensitivity analysis indicated a significantly lower stroke incidence in the liraglutide group with reduced heterogeneity (RR=0.82; 95% CI: 0.69-0.98; P=0.03; I2=22%) (Appendix D).

Figure 4. Comparison of stroke.

Figure 4

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[16,20,22-24,26-27]

CVD death: Eight studies were pooled to assess CVD death. Liraglutide significantly reduced CVD death incidence compared to the control group (RR=0.70; 95% CI: 0.57-0.85; P=0.0003; I2=65%) (Figure 5). Sensitivity analysis maintained consistent results with significantly reduced heterogeneity (RR=0.79; 95% CI: 0.71-0.88; P<0.0001; I2=0%) (Appendix E).

Figure 5. Comparison of cardiovascular disease death.

Figure 5

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[17,19,22-27]

All-cause death: Data from ten studies were aggregated to assess all-cause death. Liraglutide significantly reduced all-cause death incidence compared to the control group (RR=0.87; 95% CI: 0.80-0.94; P=0.0003; I2=0%) (Figure 6).

Figure 6. Comparison of all-cause death.

Figure 6

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[16-17,19,20-24,26-27]

Discussion

This meta-analysis aimed to assess the impact of liraglutide on CV outcomes in patients with type 2 diabetes mellitus (T2DM) with or without baseline CVD. Liraglutide demonstrated improved outcomes in MACE, myocardial infarction, CVD mortality, and all-cause mortality when compared to the control group. The two groups did not exhibit any statistically significant difference in terms of stroke outcomes. However, upon sensitivity analysis, liraglutide was associated with a decreased risk of stroke compared to the control group.

Addressing metabolic risk factors has the potential to reduce both morbidity and mortality rates in individuals with T2DM. The efficacy of GLP-1 receptor agonists (GLP-1 RA) in lowering blood pressure, HbA1c levels, and other metabolic risk markers has been established in multiple studies [28-31]. GLP-1 activates adenylate cyclase through the GLP-1 receptor (GLP-1R) and the stimulatory Gs protein, indicating its potential cardio-protective and vasodilatory actions, which might not be receptor-dependent [32-34]. Additionally, GLP-1's role in this phenomenon is plausible. The primary GLP-1 metabolite has elevated circulation levels compared to intact bioactive GLP-1. Notably, CVD and all-cause mortality have been associated with HbA1c [34- 36].

The meta-analysis of trials such as United Kingdom Prospective Diabetes Study (UKPDS), PROactive, ADVANCE, VADT, and Action to Control Cardiovascular Risk in Diabetes (ACCORD) provides evidence for the moderate advantages of glucose management in T2DM patients, as demonstrated by diverse outcomes [37]. Liraglutide treatment's efficacy in reducing CV risk biomarkers, like TNF-α and MR-proADM, has been proven in a randomized, placebo-controlled, double-blind crossover study [38]. The available data compellingly indicate that pharmacological interventions targeting HbA1c levels significantly impact CV outcomes beyond HbA1c reduction alone. Recent clinical research suggested that albiglutide, a GLP-1 RA, did not reduce MACE risk in T2DM patients [39]. Potential explanations for this discrepancy could involve the statistical power of our investigation and the influence of GLP-1 receptor agonists on heart rate, which has been linked to an increased risk of cardiovascular complications [40,41].

Several prior meta-analyses have assessed liraglutide's efficacy and safety on CV outcomes. Bethel et al. showed a significant decrease in MACE (HR 0.90, 95% CI 0.82-0.99; p=0.033) and all-cause mortality (0.88, 0.81-0.95; p=0.002), but did not find any effect of GLP-1 on myocardial infarction and stroke incidence [42]. Similarly, Giugliano et al. found reduced MACE (HR=0.86, 95% CI 0.79-0.94, P=0.006) and CV mortality, along with decreased stroke incidence, but no significant impact on myocardial infarction [43]. Qin and Song reported lower MACE and stroke incidence with GLP-1 treatment but no effect on myocardial infarction [44]. In contrast, the study by Duan et al. significantly lowered MACE, myocardial infarction, all-cause mortality, and CV mortality with liraglutide while failing to show an effect on stroke [45]. While mostly consistent, our study uniquely demonstrated a significant reduction in myocardial infarction and stroke incidence.

Beyond its immediate clinical implications, liraglutide's notable cardiovascular benefits herald a positive future for healthcare. Liraglutide's effectiveness in improving CV outcomes emphasizes the need to address metabolic diseases holistically, beyond traditional disease-specific boundaries. This discovery encourages researchers and pharmaceutical companies to explore novel therapeutic approaches that simultaneously target diabetes and cardiovascular conditions. Multi-target drugs addressing lipid profiles, CV function, and glucose metabolism interactions could revolutionize treatment approaches. Additionally, liraglutide's success may stimulate the development of personalized medicine tailored to individual metabolic and CV profiles.

Limitations

Our study is constrained by potential misdiagnosis due to varying incident CVD diagnostic criteria. In trials with smaller subgroup sizes and no prior CVD history, liraglutide's effects were less statistically significant. The high-risk focus on type 2 diabetes might limit generalizability to lower-risk populations, and medication variations could introduce bias. Some of the examined studies focused on liraglutide's impact on glycemic control and safety, indicating the need for larger, well-designed RCTs to comprehensively evaluate CV outcomes.

Conclusions

The outcomes of our thorough investigation and meta-analysis strongly support the use of liraglutide for managing CVD outcomes, given its proven safety and effectiveness. Further RCTs and additional meta-analyses are warranted to further evaluate liraglutide's therapeutic potential with the objective of enhancing the quality of life for individuals affected by CVD.

Appendices

Appendix A

Table 2. Search strategy.

Database Query Search details Results
PubMed ((((Liraglutide) AND (Diabetes Mellitus)) OR (DM)) AND (cardiovascular disease))) AND (randomized controlled trial) ((("liraglutid"[All Fields] OR "liraglutide"[MeSH Terms] OR "liraglutide"[All Fields] OR "liraglutide s"[All Fields]) AND ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields])) OR ("dyn med"[Journal] OR "dis mon"[Journal] OR "dis manag"[Journal] OR "dm"[All Fields])) AND ("cardiovascular diseases"[MeSH Terms] OR ("cardiovascular"[All Fields] AND "diseases"[All Fields]) OR "cardiovascular diseases"[All Fields] OR ("cardiovascular"[All Fields] AND "disease"[All Fields]) OR "cardiovascular disease"[All Fields]) AND ("randomized controlled trial"[Publication Type] OR "randomized controlled trials as topic"[MeSH Terms] OR "randomized controlled trial"[All Fields] OR "randomised controlled trial"[All Fields]) 1,110
Web of Science      
Embase      
Cochrane Library      
SCOPUS      
Google Scholar      
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Appendix B1 and B2

Figure 7. Quality assessment .

Figure 7

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Figure 8. Funnel plot of comparison: 1 CVD outcomes, outcome: MACE.

Figure 8

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Appendix C

Figure 9. Sensitivity analysis of the outcome of myocardial infarction.

Figure 9

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Appendix D

Figure 10. Sensitivity analysis of the outcome of stroke.

Figure 10

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Appendix E

Figure 11. Sensitivity analysis of the outcome of CVD death.

Figure 11

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The authors have declared that no competing interests exist.

Author Contributions

Concept and design:  Faraz Saleem, Hema Srikanth Vemulapalli, Jaahnavi Vajje, Wajeeh Rehman, Ghazala S. Virk, Krushi Shah, Sandipkumar S. Chaudhari, Irfan-ud-din Mian

Acquisition, analysis, or interpretation of data:  Faraz Saleem, Hema Srikanth Vemulapalli, Jaahnavi Vajje, Wajeeh Rehman, Ghazala S. Virk, Krushi Shah, Sandipkumar S. Chaudhari, Irfan-ud-din Mian

Drafting of the manuscript:  Faraz Saleem, Hema Srikanth Vemulapalli, Jaahnavi Vajje, Wajeeh Rehman, Ghazala S. Virk, Krushi Shah, Sandipkumar S. Chaudhari, Irfan-ud-din Mian

Critical review of the manuscript for important intellectual content:  Faraz Saleem, Hema Srikanth Vemulapalli, Jaahnavi Vajje, Wajeeh Rehman, Ghazala S. Virk, Krushi Shah, Sandipkumar S. Chaudhari, Irfan-ud-din Mian

Supervision:  Faraz Saleem, Hema Srikanth Vemulapalli, Jaahnavi Vajje, Sandipkumar S. Chaudhari, Irfan-ud-din Mian

References

  • 1.Type 2 diabetes: principles of pathogenesis and therapy. Stumvoll M, Goldstein BJ, van Haeften TW. Lancet. 2005;365:1333–1346. doi: 10.1016/S0140-6736(05)61032-X. [DOI] [PubMed] [Google Scholar]
  • 2.The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Weyer C, Bogardus C, Mott DM, Pratley RE. J Clin Invest. 1999;104:787–794. doi: 10.1172/JCI7231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Cowie CC, Casagrande SS, Geiss LS. Diabetes in America. Bethesda: National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018. Prevalence and incidence of type 2 diabetes and prediabetes. [PubMed] [Google Scholar]
  • 4.Diabetes structured self-management education programmes: a narrative review and current innovations [published correction appears in. Chatterjee S, Davies MJ, Heller S, Speight J, Snoek FJ, Khunti K. Lancet Diabetes Endocrinol. 2018;2:130–142. doi: 10.1016/S2213-8587(17)30239-5. [DOI] [PubMed] [Google Scholar]
  • 5.Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lago RM, Singh PP, Nesto RW. Lancet. 2007;370:1129–1136. doi: 10.1016/S0140-6736(07)61514-1. [DOI] [PubMed] [Google Scholar]
  • 6.Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. Nissen SE, Wolski K. N Engl J Med. 2007;356:2457–2471. doi: 10.1056/NEJMoa072761. [DOI] [PubMed] [Google Scholar]
  • 7.Glucagon-like peptide-1 receptor agonists: a class update for treating type 2 diabetes. Lovshin JA. Can J Diabetes. 2017;41:524–535. doi: 10.1016/j.jcjd.2017.08.242. [DOI] [PubMed] [Google Scholar]
  • 8.Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. J Clin Endocrinol Metab. 1986;63:492–498. doi: 10.1210/jcem-63-2-492. [DOI] [PubMed] [Google Scholar]
  • 9.Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? Grieve DJ, Cassidy RS, Green BD. Br J Pharmacol. 2009;157:1340–1351. doi: 10.1111/j.1476-5381.2009.00376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Liraglutide for the treatment of type 2 diabetes mellitus: a meta-analysis of randomized placebo-controlled trials. Du Q, Wang YJ, Yang S, Zhao YY, Han P. Adv Ther. 2014;31:1182–1195. doi: 10.1007/s12325-014-0164-2. [DOI] [PubMed] [Google Scholar]
  • 11.Liraglutide for Type 2 diabetes and obesity: a 2015 update. Iepsen EW, Torekov SS, Holst JJ. Expert Rev Cardiovasc Ther. 2015;13:753–767. doi: 10.1586/14779072.2015.1054810. [DOI] [PubMed] [Google Scholar]
  • 12.Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. Robinson LE, Holt TA, Rees K, Randeva HS, O'Hare JP. BMJ Open. 2013;3 doi: 10.1136/bmjopen-2012-001986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Page MJ, McKenzie JE, Bossuyt PM, et al. BMJ. 2021;372:0. doi: 10.1186/s13643-021-01626-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Higgins JP, Altman DG, Gøtzsche PC, et al. BMJ. 2011;343:0. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU) Marre M, Shaw J, Brändle M, et al. Diabet Med. 2009;26:268–278. doi: 10.1111/j.1464-5491.2009.02666.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Nauck M, Frid A, Hermansen K, et al. Diabetes Care. 2009;32:84–90. doi: 10.2337/dc08-1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Russell-Jones D, Vaag A, Schmitz O, et al. Diabetologia. 2009;52:2046–2055. doi: 10.1007/s00125-009-1472-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD) Zinman B, Gerich J, Buse JB, et al. Diabetes Care. 2009;32:1224–1230. doi: 10.2337/dc08-2124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Pratley RE, Nauck M, Bailey T, et al. Lancet. 2010;234:1447–1456. doi: 10.1016/S0140-6736(10)60307-8. [DOI] [PubMed] [Google Scholar]
  • 20.Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Seino Y, Rasmussen MF, Nishida T, Kaku K. Curr Med Res Opin. 2010;26:1013–1022. doi: 10.1185/03007991003672551. [DOI] [PubMed] [Google Scholar]
  • 21.Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B. Diabetes Obes Metab. 2011;13:348–356. doi: 10.1111/j.1463-1326.2010.01356.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Liraglutide and cardiovascular outcomes in type 2 diabetes. Marso SP, Daniels GH, Brown-Frandsen K, et al. N Engl J Med. 2016;375:311–322. doi: 10.1056/NEJMoa1603827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke. Verma S, Poulter NR, Bhatt DL, et al. Circulation. 2018;138:2884–2894. doi: 10.1161/CIRCULATIONAHA.118.034516. [DOI] [PubMed] [Google Scholar]
  • 24.Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease. Mann JF, Fonseca V, Mosenzon O, et al. Circulation. 2018;138:2908–2918. doi: 10.1161/CIRCULATIONAHA.118.036418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Cardiovascular outcomes in patients who experienced a myocardial infarction while treated with liraglutide versus placebo in the LEADER trial. Nauck MA, Tornøe K, Rasmussen S, Treppendahl MB, Marso SP. Diab Vasc Dis Res. 2018;15:465–468. doi: 10.1177/1479164118783935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Effect of liraglutide on cardiovascular outcomes in elderly patients: a post hoc analysis of a randomized controlled trial. Gilbert MP, Bain SC, Franek E, et al. Ann Intern Med. 2019;170:423–426. doi: 10.7326/M18-1569. [DOI] [PubMed] [Google Scholar]
  • 27.Effects of liraglutide on cardiovascular outcomes in patients with diabetes with or without heart failure. Marso SP, Baeres FM, Bain SC, et al. J Am Coll Cardiol. 2020;75:1128–1141. doi: 10.1016/j.jacc.2019.12.063. [DOI] [PubMed] [Google Scholar]
  • 28.Controversies in the cardiovascular management of type 2 diabetes. Opie LH, Yellon DM, Gersh BJ. Heart. 2011;97:6–14. doi: 10.1136/hrt.2010.214031. [DOI] [PubMed] [Google Scholar]
  • 29.The effect of glucagon-like peptide 1 on cardiovascular risk. Sivertsen J, Rosenmeier J, Holst JJ, Vilsbøll T. Nat Rev Cardiol. 2012;9:209–222. doi: 10.1038/nrcardio.2011.211. [DOI] [PubMed] [Google Scholar]
  • 30.Impact of dietary and metabolic risk factors on cardiovascular and diabetes mortality in South Asia: analysis from the 2010 Global Burden of Disease study. Yakoob MY, Micha R, Khatibzadeh S, et al. Am J Public Health. 2016;106:2113–2125. doi: 10.2105/AJPH.2016.303368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen YT, Shannon RP. J Pharmacol Exp Ther. 2006;317:1106–1113. doi: 10.1124/jpet.106.100982. [DOI] [PubMed] [Google Scholar]
  • 32.Effects of treatment with liraglutide on oxidative stress and cardiac natriuretic peptide levels in patients with type 2 diabetes mellitus. Okada K, Kotani K, Yagyu H, Ando A, Osuga J, Ishibashi S. Endocrine. 2014;47:962–964. doi: 10.1007/s12020-014-0246-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Impact of dietary and metabolic risk factors on cardiovascular and diabetes mortality in South Asia: analysis from the 2010 Global Burden of Disease study. Pfeffer MA, Claggett B, Diaz R, et al. N Engl J Med. 2015;373:2247–2257. doi: 10.2105/AJPH.2016.303368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Effects of incretin-based therapy in patients with heart failure and myocardial infarction. Mikhail N. Endocrine. 2014;47:21–28. doi: 10.1007/s12020-014-0175-4. [DOI] [PubMed] [Google Scholar]
  • 35.Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Ann Intern Med. 2004;141:413–420. doi: 10.7326/0003-4819-141-6-200409210-00006. [DOI] [PubMed] [Google Scholar]
  • 36.Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. Rawshani A, Rawshani A, Franzén S, et al. N Engl J Med. 2018;379:633–644. doi: 10.1056/NEJMoa1800256. [DOI] [PubMed] [Google Scholar]
  • 37.Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Ray KK, Seshasai SR, Wijesuriya S, et al. Lancet. 2009;373:1765–1772. doi: 10.1016/S0140-6736(09)60697-8. [DOI] [PubMed] [Google Scholar]
  • 38.Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub-analysis of a randomized, placebo-controlled, double-blind, crossover trial. von Scholten BJ, Persson F, Rosenlund S, et al. Diabetes Obes Metab. 2017;19:901–905. doi: 10.1111/dom.12884. [DOI] [PubMed] [Google Scholar]
  • 39.Cardiovascular safety of albiglutide in the Harmony programme: a meta-analysis. Fisher M, Petrie MC, Ambery PD, Donaldson J, Ye J, McMurray JJ. Lancet Diabetes Endocrinol. 2015;8:697–703. doi: 10.1016/S2213-8587(15)00233-8. [DOI] [PubMed] [Google Scholar]
  • 40.Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Cooney MT, Vartiainen E, Laatikainen T, Juolevi A, Dudina A, Graham IM. Am Heart J. 2010;159:612–619. doi: 10.1016/j.ahj.2009.12.029. [DOI] [PubMed] [Google Scholar]
  • 41.Heart rate as a risk factor for cardiovascular disease. Perret-Guillaume C, Joly L, Benetos A. Prog Cardiovasc Dis. 2009;52:6–10. doi: 10.1016/j.pcad.2009.05.003. [DOI] [PubMed] [Google Scholar]
  • 42.Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Bethel MA, Patel RA, Merrill P, et al. Lancet Diabetes Endocrinol. 2018;6:105–113. doi: 10.1016/S2213-8587(17)30412-6. [DOI] [PubMed] [Google Scholar]
  • 43.GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Giugliano D, Scappaticcio L, Longo M, et al. Cardiovasc Diabetol. 2021;20:189. doi: 10.1186/s12933-021-01366-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials. Qin J, Song L. BMC Endocr Disord. 2022;22:125. doi: 10.1186/s12902-022-01036-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Cardiovascular outcomes of liraglutide in patients with type 2 diabetes: A systematic review and meta-analysis. Duan CM, Wan TF, Wang Y, Yang QW. Medicine (Baltimore) 2019;98:0. doi: 10.1097/MD.0000000000017860. [DOI] [PMC free article] [PubMed] [Google Scholar]

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