Skip to main content
Download PDF
Download ePub

Impact of baseline FIB-4 score on efpeglenatide benefits on cardiovascular outcomes in people with type 2 diabetes: a participant-level exploratory analysis of the AMPLITUDE-O trial

Cardiovascular Diabetology volume 23, Article number: 352 (2024) Cite this article

Abstract

Aims

To estimate the incidence of major adverse cardiovascular events (MACE), expanded MACE, and MACE or Death across Fibrosis- 4 score (FIB-4) categories in people with type 2 diabetes and to determine whether efpeglenatide’s effect varies with increasing FIB-4 severity.

Materials and methods

AMPLITUDE-O trial data were used to estimate the relationship of FIB-4 score categories to the hazard of MACE, expanded MACE, and MACE or death. Interactions on these outcomes between baseline FIB-4 score, and between FIB-4 score and efpeglenatide were also assessed.

Results

Baseline FIB-4 score was available for 4059 participants (99.6%) allowing subdivision of the population in tertiles. During a median follow-up of 1.8 years, numerical increases in the incidence of all 3 outcomes did not change significantly across tertiles of FIB-4 score (P for trend ≥ 0.25) with negligible relationship of the score to incident outcomes (MACE HR, per 1 SD higher score, 95% CI: 1.00, 0.89–1.13). Efpeglenatide’s effect on all MACE outcomes did not vary across FIB-4 tertiles (all interaction p values ≥ 0.64).

Conclusions

In high-risk people with type 2 diabetes, the degree of liver fibrosis, as estimated by FIB-4 score, was not related to incident cardiovascular outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of FIB-4 category.

Introduction

Cardiovascular risk in Type 2 diabetes (T2DM) is largely due to the concomitance of multiple risk factors, with a prominent role played by glycemic control, LDL-cholesterol, blood pressure, and smoking, i.e., the so-called traditional CV risk factors [1]. However, more recently other factors have been suggested to worsen CV risk in T2DM. Among them, a role of NAFLD/NASH, now referred to as Metabolic-associated Fatty Liver Disease (MAFLD), albeit debated [2], has been claimed [3].

In people with T2DM, the prevalence of MAFLD is at least twofold higher than in the general population [4], ranging from 55 to 70% [5]. Furthermore, people with T2DM are more likely to develop MASH (30–40%) and to progress toward fibrosis and cirrhosis [4, 5] compared to those without. MAFLD has been associated with increased risk of fatal or non-fatal cardiovascular (CV) events, irrespective of concomitant risk factors, including diabetes itself [6, 7], although the quality of the evidence remains sub-optimal [2].

The AMPLITUDE-O trial clearly showed that efpeglenatide (either 4 or 6 mg weekly) reduced the primary outcome of major adverse CV events (MACE) as well as all the pre-specified secondary outcomes versus placebo [8]. In the trial, a fibrosis 4 [FIB-4] score was calculated in all participants. Although, liver biopsy and/or MRI are considered gold-standard for MAFLD diagnosis and ultrasonography is commonly used as first-line diagnostic tool, non-invasive scores, based on serum biomarkers, have been proposed including FIB-4 [7, 9] and several cut-off values have been proposed to establish different stages of fibrosis in patients with MAFLD [10]. Moreover, the World Health Organization and various scientific associations have proposed FIB-4 as an alternative method to identify individuals with possible liver fibrosis [11, 12].

Accordingly, we sought to investigate the association of FIB-4 with MACE and other secondary outcomes in AMPLITUDE-O trial, as well as evaluate if different levels of FIB-4 score modifies the effect of efpeglenatide on these outcomes.

Methods

AMPLITUDE-O (NCT03496298) was an event-driven, double-blind, randomized controlled trial conducted in 344 sites located in 28 countries. It was designed to determine the cardiovascular effects of the once weekly GLP1 receptor agonist efpeglenatide, (administered subcutaneously at the dose of 4 and 6 mg with matching placebo) in people with T2DM with prior cardiovascular disease or evidence of chronic kidney disease [8]. To be included in the trial, participants had to be 18 years or older with established previous coronary artery disease, stroke, or peripheral artery disease or older than 50 years if male or 55 years if female with an eGFR of 25–59.9 mL/min/1.73m2 plus one or more cardiovascular risk factors [13]. Individuals with ALT or AST > 3 times the upper limit of the normal range (ULN) and those with a total bilirubin > 1.5 times the ULN (except in case of documented Gilbert’s syndrome) were excluded from participation in the trial. A total of 4076 participants randomly assigned to efpeglenatide (n = 2717) or placebo (n = 1359) and followed up for a median of 1.81 years. The primary outcome was the first occurrence of 3-point MACE (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes), and the main results of the trial have been described previously [8].

The FIB-4 score, an index reflecting hepatic fibrosis [14], was calculated at baseline as [age (years) x aspartate aminotransferase (U/L)] / [platelet count (109/L) x alanine transaminase (U/L)1/2]. The population was then divided into FIB-4 tertiles to maximize power across groups.

Outcomes

We analyzed the effect of efpeglenatide versus placebo on three major AMPLITUDE-O outcomes that were significantly reduced by efpeglenatide within subgroups defined by FIB-4 tertiles. These included the major adverse cardiovascular events (MACE), defined as a non-fatal myocardial infarction, a non-fatal stroke, or death from CV or undetermined causes; an expanded MACE (MACE, coronary revascularization, or hospitalization for unstable angina); and the composite of MACE or non-CV death.

Statistical analysis

Continuous variables were summarized with either means and standard deviations or medians and interquartile ranges, and categorical variables were summarized as counts and percentages. Kaplan Meier curves were used to display cumulative risks. Cox proportional hazards models adjusted for region were used to estimate hazard ratios and 95% confidence intervals overall and within subgroups defined by baseline FIB-4 tertiles.

Hazard ratios and 95% confidence intervals were estimated using the same Cox proportional hazards models that were used to estimate the effect of efpeglenatide in previous publications, with the addition of the FIB4 score and a score-intervention interaction term. As previously reported all models were adjusted for region (North America, Latin America, Europe, other), and the randomization stratification factor regarding the use of SGLT2-inhibitors. All analyses were conducted using SAS software version 9.4 (SAS Institute).

Results

FIB-4 score was calculated in 4059 participants (99.6%) and yielded a mean value of 1.26 ± 0.69 allowing the identification of 3 tertiles: ≤0.94 (FIB-4 Lowest); 0.95–1.35 (FIB-4 Middle), and > 1.35 (FIB-4 Highest). Baseline characteristics for participants in each FIB-4 tertiles are summarized in Table 1. Age, diabetes duration, and male gender increased across tertiles. As expected, across tertile there was a progressive increase in liver enzyme levels and decrease of platelet count. Higher tertiles were associated with poorer eGFR, but better lipid profile, and HbA1c levels. No difference was apparent across tertiles as far as medications are concerned with the exception of lower use of metformin and greater use of beta blockers from the lowest to the highest FIB-4 tertile.

Table 1 Baseline characteristics according to Baseline FIB-4 score
Full size table

Baseline FIB-4 score and incident CV outcomes

Table 2 illustrates the incidence rate of MACE, expanded MACE and MACE or death according to baseline FIB-4 score. Although there was a numerical trend for an increasing incidence of all three outcomes with the numerically highest rate occurring for the FIB-4 highest tertile, the differences between tertiles were not statistically significant. There was no relationship between the FIB-4 score and incident MACE outcomes (HR, per 1 SD higher score, 95% CI: 1.00, 0.89–1.13) (Table 3).

Table 2 Incidence of various outcomes according to Baseline FIB-4 score
Full size table
Table 3 Relationship of FIB-4 score to Incident Outcomes
Full size table

Effect of efpeglenatide on clinical outcomes

In the whole study population, efpeglenatide treatment (4 and 6 mg once weekly) was associated with significant risk reduction for MACE (HR 0.73 95% CI 0.58–0.92), expanded MACE (HR 0.79, 0.65–0,96), and MACE or death (HR 0.73, 0.59–0.91). When assessed within FIB-4 score tertiles, the HR of the intervention on the 3 main outcomes was similar across the three groups with no nominally significant heterogeneity (Fig. 1). The results were similar when the 4 mg and 6 mg efpeglenatide doses were assessed separately (Suppl Tables 1 and 2).

Fig. 1
figure 1

Exploratory analysis of incident MACE, Expanded MACE, and MACE or death in the whole AMPLITUDE-O study population and upon stratification by tertiles of FIB-4 score

Full size image

Discussion

Within the population of people with T2DM and established CV disease of the AMPLITUDE-O trial, the FIB-4 score was not associated with the incidence rate of MACE, extended MACE, or MACE and death. Moreover, the beneficial effect of efpeglenatide was similar across tertiles of baseline FIB-4 score.

The finding that baseline FIB-4 score is not associated with increasing CV risk may sound at odds with prior observations linking the degree of lipid deposition, fibrosis, and concomitant inflammation with higher risk to experience CV events and CV death [15]. Although the reasons for this discrepancy may not be readily apparent, it is worth highlighting that 90% of the subjects included in the AMPLITUDE-O trial had an established CV event representing a population at very high risk, (i.e. potential collider bias) which may have resulted in an attenuation of other accelerating factors such as MAFLD/ NASH. Even so, the results are of value since traditional risk factors (e.g. BP, lipid levels, CRP levels) remains predictive in the secondary prevention setting as recently suggested in a very large population-based analysis [2]. It is also worth highlighting that only a minority of the AMPLITUDE-O population met the high-risk FIB-4 score > 2.67, as recently proposed by Anstee and colleagues [10].

The CV protective effect of long-acting GLP-1RA has been reported in several CVOTs [16] including AMPLITUDE-O [8]. Many mechanisms are likely to account for the CV protection of GLP1-RAs, including improved glycemic control, body weight reduction, improved lipid profile, meaningful body weight loss, reduced inflammatory response along with a possible direct anti-atherogenic action and a direct effect on endothelial function [17]. In people with T2DM, GLP1-RAs have been claimed to exert an overall 3% reduction of intra-hepatic fat along with reduction of inflammatory markers, and some metabolic indices and MAFLD [18], which could be expected to contribute reducing CV risk, though no direct evidence has been so far provided. Therefore, specific trials among individuals with MAFLD assessing the effect of GLP1-RAs on liver fat deposition and fibrosis and their relationship with CV events may be necessary. A first study of this kind is the Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis (ESSENCE) trial (NCT 04822181) recruiting subjects with histological evidence of MAFLD and hepatic fibrosis, randomized to treatment with once weekly semaglutide (2.4 mg) or placebo [19].

In our post-hoc analysis of the AMPLITUDE-O trial, the CV protective effect of efpeglenatide was not affected by the level of baseline FIB-4 score and across the FIB-4 score tertiles the risk reduction of CV outcomes was similar to the one observed in the whole population. Our results are in keeping with those of a retrospective, population-based, nationwide cohort study assessing the effect of GLP-1RAs compared to DPP4-inhibitors on CV events in people with and without MAFLD [20]. The study, involving > 35.000 participants, confirmed the superiority of GLP1-RAs vs. DPP4-inhibitors in reducing the risk of MACE (HR 0.49, 95% CI, 0.48–0.81) but did not find heterogeneity based on the MAFLD status. Therefore, the results obtained within a randomized controlled trial and those obtained in the real-world setting concur to suggest that GLP1-RAs exert a similar benefit in people with T2DM irrespective of the presence and severity of MAFLD. A similar conclusion has come from a recent population-based propensity-matched retrospective cohort study involving 2,835,398 patients with both MAFLD and T2DM showing that GLP-1RAs are associated with lower incidences of adverse MACE and all-cause mortality compared with metformin or glucose-lowering medications but with no difference as compared to inhibitors of Sodium-Glucose Cotransporter-2 (SGLT2i) [21]. Nonetheless, no stratification for the degree of fat deposition or fibrosis was available in that study. Liver fibrosis in people with MAFLD/NASH has been claimed to confer a greater risk of CV disease and mortality [22, 23], particularly in those with stages 3 and 4 fibrosis [22, 24]. However, whether fibrosis can be effectively reduced by GLP1-RAs is not that clear. With respect to this, it is interesting to note that, in a phase 2 trial involving individuals with NASH, treatment with semaglutide induced NASH resolution in a greater percentage of people than placebo, though no difference in the percentage of patients with improved fibrosis could be detected [25].

Our analysis has some limitations. First, the observation time was relatively short with a 1.8-year median follow-up. A limitation also could be the use of a fibrosis score rather than a direct imaging-aided assessment of NAFLD/NASH. However, the FIB-4 score is an accepted first-line assessments in people with MASLD and T2DM [9, 26,27,28,29]. Second, most the people with T2DM in the AMPLITUDE-O trial fell in the low-moderate category of FIB-4 related risk, which may have limited the ascertainment of the impact of efpeglenatide in people with a more severe degree of liver fibrosis. Finally, FIB-4 gauges the degree of liver fibrosis and whether surrogate indexes of hepatic steatosis may yield similar results remains to be evaluated.

Strengths of these analyses include the high follow-up rate, and the inclusion of 97.7% of all AMPLITUDE-O participants and 97.7% and 98.0% of all measured MACE and kidney outcomes, respectively. Given the high prevalence of MAFLD in people with T2DM, it is likely that all GLP1-RA CVOTs must have been populated by a large proportion of individuals with MAFLD/NASH. Nonetheless, to the best of our knowledge, no CVOT has been able to report the proportion of study subjects with MAFLD, and no analyses of primary and secondary outcomes by the presence or absence of MAFLD is currently available. Therefore, this is the first report on the effect of a GLP1-RA, i.e., efpeglenatide on CV events after stratification of the study population by an accepted surrogate index of MAFLD risk. Although a GLP1 receptor agonist class effect could be envisioned, our results only pertain to efpeglenatide and whether any potential differential effect may be exerted by other agents of the class remains to be evaluated.

In conclusion, this exploratory analysis of the AMPLITUDE-O trial showed that the degree of MAFLD, as estimated by the FIB-4 score, was not related to incident CV outcomes. The efficacy of efpeglenatide was independent of the degree of liver fibrosis, as determined by the FIB-4 score.

Data availability

Data is provided within supplementary information files.

References

  1. Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and Cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379:633–44.

    Article  PubMed  Google Scholar 

  2. Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, Pasqua A, Lapi F, Rijnbeek P, Mosseveld M, Avillach P, Egger P, Dhalwani NN, Kendrick S, Celis-Morales C, Waterworth DM, Alazawi W, Sattar N. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults. BMJ. 2019;367:l5367.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhou XD, Targher G, Byrne CD, Somers V, Kim SU, Chahal CAA, Wong VW, Cai J, Shapiro MD, Eslam M, Steg PG, Sung KC, Misra A, Li JJ, Brotons C, Huang Y, Papatheodoridis GV, Sun A, Yilmaz Y, Chan WK, Huang H, Méndez-Sánchez N, Alqahtani SA, Cortez-Pinto H, Lip GYH, de Knegt RJ, Ocama P, Romero-Gomez M, Fudim M, Sebastiani G, Son JW, Ryan JD, Ikonomidis I, Treeprasertsuk S, Pastori D, Lupsor-Platon M, Tilg H, Ghazinyan H, Boursier J, Hamaguchi M, Nguyen MH, Fan JG, Goh GB, Al Mahtab M, Hamid S, Perera N, George J, Zheng MH. An international multidisciplinary consensus statement on MAFLD and the risk of CVD. Hepatol Int. 2023;17:773–91.

    Article  PubMed  Google Scholar 

  4. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793–801.

    Article  PubMed  Google Scholar 

  5. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10:284–96.

    Article  PubMed  Google Scholar 

  6. Mantovani A, Csermely A, Petracca G, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6:903–13.

    Article  PubMed  Google Scholar 

  7. Duell PB, Welty FK, Miller M, et al. American Heart Association Council on arteriosclerosis, thrombosis and vascular biology; Council on hypertension; Council on the kidney in cardiovascular disease; Council on lifestyle and cardiometabolic health; and Council on peripheral vascular disease. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e168–85.

    CAS  PubMed  Google Scholar 

  8. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385:896–907.

    Article  CAS  PubMed  Google Scholar 

  9. European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016;59:1121–40.

    Article  Google Scholar 

  10. Anstee QM, Berentzen TL, Nitze LM, Jara M, Jensen AB, Kjær MS, Mangla KK, Tarp JM, Khunti K. Prognostic utility of Fibrosis-4 index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study. Lancet Reg Health Eur. 2023;36:100780.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang L, Wang M, Zhao W, et al. Key points of 2015 EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver severity and prognosis. J Hepatol. 2015;63:237–64.

    Article  Google Scholar 

  12. Zarski JP, Sturm N, Desmorat H, et al. Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study. Liver Int. 2010;30:1049–58.

    Article  CAS  PubMed  Google Scholar 

  13. Gerstein HC, Branch K, Heenan L, Del Prato S, Khurmi NS, Lam CSP, Pratley R, Rosenstock J, Sattar N. Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist. Diabetes Obes Metab. 2021;23(2):318–23.

    Article  CAS  PubMed  Google Scholar 

  14. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.

    Article  CAS  PubMed  Google Scholar 

  15. Chew NWS, Pan XH, Chong B, Chandramouli C, Muthiah M, Lam CSP. Type 2 diabetes mellitus and cardiometabolic outcomes in metabolic dysfunction-associated steatotic liver disease population. Diabetes Res Clin Pract. 2024;211:111652.

    Article  CAS  PubMed  Google Scholar 

  16. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, Lam CSP, Lopes RD, McMurray JJV, Pratley RE, Rosenstock J, Gerstein HC. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653–62.

    Article  CAS  PubMed  Google Scholar 

  17. Dardano A, Bianchi C, Garofolo M, Del Prato S. The current landscape for diabetes treatment: preventing diabetes-associated CV risk. Atherosclerosis. 2024 Apr;23:117560. Online ahead of print.

  18. Dai Y, He H, Li S, Yang L, Wang X, Liu Z, An Z. Comparison of the efficacy of Glucagon-Like Peptide-1 receptor agonists in patients with metabolic Associated fatty liver disease: updated systematic review and Meta-analysis. Front Endocrinol (Lausanne). 2021;11:622589.

    Article  PubMed  Google Scholar 

  19. https://clinicaltrials.gov/study/NCT04822181?cond=NASH%20%20Nonalcoholic%20Steatohepatitis&intr=Semaglutide&rank=3. Accessed on May14, 2024.

  20. Bea S, Jeong HE, Filion KB, Yu OH, Cho YM, Lee BH, Chang Y, Byrne CD, Shin JY. Outcomes of SGLT-2i and GLP-1RA therapy among patients with type 2 diabetes and varying NAFLD Status. JAMA Netw Open. 2023;6(12):e2349856.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Krishnan A, Schneider CV, Hadi Y, Mukherjee D, AlShehri B, Alqahtani SA. Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study. Diabetologia. 2024;67(3):483–93.

    Article  CAS  PubMed  Google Scholar 

  22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97. e310.

    Article  PubMed  Google Scholar 

  23. Vieira Barbosa J, Milligan S, Frick A, et al. Fibrosis-4 index can independently predict major adverse cardiovascular events in nonalcoholic fatty liver disease. Am J Gastroenterol. 2022;117:453–61.

    Article  PubMed  Google Scholar 

  24. Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–54.

    Article  CAS  PubMed  Google Scholar 

  25. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA. NN9931-4296 investigators. A placebo-controlled trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113–24.

    Article  CAS  PubMed  Google Scholar 

  26. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797–835.

    Article  PubMed  Google Scholar 

  27. European Association for the Study of the Liver (EASL). EASL Clinical Practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis– 2021 update. J Hepatol. 2021;75:659–89.

    Article  Google Scholar 

  28. Kanwal F, Shubrook JH, Adams LA, et al. Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021;161:1657–69.

    Article  CAS  PubMed  Google Scholar 

  29. ElSayed NA, Aleppo G, Aroda VR et al. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes–2023. Diabetes Care. 2023;46(Suppl 1):S49–S67.

Download references

Funding

The AMPLITUDE O trial was funded by Sanofi and the analyses presented here were funded by Hanmi. All statistical analyses for this and other papers describing the AMPLITUDE O results were conducted by the Population Health Research Institute in Hamilton Canada.

Author information

Authors and Affiliations

  1. Interdisciplinary Research Center “Health Science”, Sant’Anna School of Advanced Studies, Piazza Martiri della Libertà, 33, 56127, Pisa, Italy

    Stefano Del Prato

  2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada

    Zhuoru Li, Chinthanie Ramasundarahettige & Hertzel C. Gerstein

  3. Division of Cardiology, University of Washington, Seattle, WA, USA

    Kelley R. H. Branch

  4. National Heart Centre Singapore and Duke-National University of Singapore, Singapore, Singapore

    Carolyn S. P. Lam

  5. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA

    Renato D. Lopes

  6. AdventHealth Translational Research Institute, Orlando, FL, USA

    Richard Pratley

  7. Velocity Clinical Research at Medical City, Dallas, TX, USA

    Julio Rosenstock

  8. School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK

    Naveed Sattar

Authors
  1. Stefano Del Prato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhuoru Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chinthanie Ramasundarahettige
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelley R. H. Branch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carolyn S. P. Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Renato D. Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard Pratley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julio Rosenstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naveed Sattar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hertzel C. Gerstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SDP and HCG conceived the research hypothesis; HCG, ZL and CR performed statistical analysis; SDP and HCG wrote the manuscript, KRHB, CSPL, and NS assisted in writing the manuscript; RP and JR reviewed and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Stefano Del Prato.

Ethics declarations

Competing interests

SDP has served as president of EASD/European Foundation for the Study of Diabetes (EFSD) (2020–2022); has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as advisor for Abbott, Amarin Corporation, Amplitude, Applied Therapeutics, AstraZeneca, Biomea Fusion, Eli Lilly & Co., EvaPharma, Menarini International, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. KRHB has research grants from the NIH, Population Health Research Institute, Bayer, Sanofi, Eli Lilly, Kestra, Medic One Foundation and consulting fees from Bayer, Janssen, Amgen, Sana, Kestra, Hanmi. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from NovoNordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder & non-executive director of Us2.ai. RDL has received research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk. RP has received the following: speaker fees from Lilly, Merck and Novo Nordisk; consulting fees from Bayer AG, Bayer HealthCare Pharmaceuticals, Inc., Corcept Therapeutics Incorporated, Dexcom, Endogenex, Inc., Gasherbrum Bio, Inc., Genprex, Getz Pharma, Hanmi Pharmaceutical Co., Hengrui (USA) Ltd., Intas Pharmaceuticals, Inc., Lilly, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals Inc., Sanofi, and Sun Pharmaceutical Industries; and grants from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Inc., Fractyl, Lilly, Novo Nordisk, and Sanofi. JR has served on scientific advisory panels for Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Endogenex, Hanmi, Novo Nordisk, Oramed, Regor, Sanofi, Structure Therapeutics, and Zealand Pharma; and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, and Sanofi. NS has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing education grants from Eli Lilly, Abbott, Sanofi, Novo Nordisk and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Sanofi, Carbon Brand, and Jiangsu Hanson; and consulting fees from Abbott, Bayer, Eli Lilly, Novo Nordisk, Pfizer, Sanofi, Kowa, and Hanmi.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Del Prato, S., Li, Z., Ramasundarahettige, C. et al. Impact of baseline FIB-4 score on efpeglenatide benefits on cardiovascular outcomes in people with type 2 diabetes: a participant-level exploratory analysis of the AMPLITUDE-O trial. Cardiovasc Diabetol 23, 352 (2024). https://doi.org/10.1186/s12933-024-02432-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12933-024-02432-7

Keywords

Cardiovascular Diabetology

ISSN: 1475-2840