Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 The “legacy effect” describes the long-term benefits that may persist for many years after the end of an intervention period. There is sufficient data to suggest the existence of a legacy effect after intensive intervention on cardiovascular risk factors. + 1613 word(s) 1613 2020-11-12 14:19:21 |
2 format correct + 4 word(s) 1617 2020-11-16 06:54:09 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Viñas Esmel, E.; Naval Álvarez, J.; Sacanella Meseguer, E. Legacy Effect in Cardiovascular Disease. Encyclopedia. Available online: (accessed on 21 June 2024).
Viñas Esmel E, Naval Álvarez J, Sacanella Meseguer E. Legacy Effect in Cardiovascular Disease. Encyclopedia. Available at: Accessed June 21, 2024.
Viñas Esmel, Esther, José Naval Álvarez, Emilio Sacanella Meseguer. "Legacy Effect in Cardiovascular Disease" Encyclopedia, (accessed June 21, 2024).
Viñas Esmel, E., Naval Álvarez, J., & Sacanella Meseguer, E. (2020, November 15). Legacy Effect in Cardiovascular Disease. In Encyclopedia.
Viñas Esmel, Esther, et al. "Legacy Effect in Cardiovascular Disease." Encyclopedia. Web. 15 November, 2020.
Legacy Effect in Cardiovascular Disease

The "legacy effect" describes the long-term benefits that may persist for many years after the end of an intervention period, involving different biological processes. The legacy effect in cardiovascular disease (CVD) prevention has been evaluated by a limited number of studies, mostly based on pharmacological interventions, while few manuscripts on dietary interventions have been published. Most of these studies are focused on intensive treatment regimens, whose main goal is to achieve tight control of one or more cardiovascular risk factors. 

legacy effect metabolic memory cardiovascular disease diet diabetes hypertension dyslipidaemia

1. Introduction 

Cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality, accounting for 30% of all deaths worldwide. The intensive management of cardiovascular risk factors is required to reduce its incidence, and some authors suggest that achieving tight control at early stages of the disease, before vascular damage has developed, is a determinant of outcomes [1].

The legacy effect concept refers to long-term sustained benefits after a period of intensive treatment intervention, even after cessation of the intervention [2]. Initially described in diabetic patients, it has also been observed in patients with hypertension or hypercholesterolemia [3]. Moreover, the concept of metabolic memory, mostly described in the study of diabetic models, refers to DNA’s ability to store information related to prior poor metabolic control; for example, persistent adverse effects of hyperglycaemia may reduce the potential benefit of subsequent improvements in glucose control, and induce the development of vascular complications in target organs [4][5]. Therefore, achieving good glycaemic control in the early stages of diabetes could be critical in preventing late-stage complications [6][7].

2. Discussion

Most studies evaluating the legacy effect on the primary or secondary prevention of CVD are clinical trials promoted and financed by the pharmaceutical industry in which an observational study has continued at the end of the intervention phase. As a consequence, the legacy effect has been assessed mainly after pharmacological intervention. Few studies have been carried out after a nutritional intervention, and most focused on animal and diabetic models.

Different clinical outcomes have been evaluated, including microvascular complications (retinopathy, neuropathy, nephropathy), major cardiovascular events (heart failure, myocardial infarction, stroke, and ischemic gangrene) and mortality, as well as analytical parameters. The results obtained have been quite heterogeneous, probably due to differences in the baseline characteristics of the patients included, the type and duration of the interventions, and post-trial follow-up. In general terms, the legacy effect has been observed to be less intense than that achieved in the intervention phase and tends to diminish with longer follow-up. All the data suggest that this effect is greater and longer lasting in patients without known CVD undergoing intensive therapy for recent-onset diabetes, hypertension or dyslipidaemia.

A limited number of studies related to the legacy effect after nutritional intervention have been published to date. In studies performed with rats and mice, some authors have demonstrated that after calorie restriction (CR; reduction of daily caloric intake by approximately 25%) or intermittent fasting, glycaemic control and insulin resistance could improve for several weeks. The evidence in humans is lacking, as health benefits of CR or intermittent fasting have been evaluated mainly in observational studies and a single clinical trial (CALERIE Study). The effect during the intervention period appears to be favourable but disappears shortly after the intervention ends. Therefore, CR or intermittent fasting has not been shown to generate a legacy effect in humans [8]. In addition, we would like to highlight safety concerns regarding intermittent fasting in patients with diabetes mellitus due to the higher risk of hypoglycemia. Data from the Oslo Cardiovascular study suggest that systematic advice on a healthy diet and smoking cessation for five years could be associated with a legacy effect translated into a reduced risk of cardiovascular mortality in the next 40 years. However, it is difficult to ensure that no confounding factors could have altered these results [9]. Currently, there are no data available on the possible legacy effect in other, more recent nutritional intervention studies, such as the PREDIMED (Prevención con Dieta Mediterránea) Study [10]. The limited scientific evidence published on the possible legacy effect in CVD prevention after a dietary intervention may be due to multiple factors, including: difficulty in maintaining high adherence to the proposed nutritional intervention, absence of specific biomarkers of dietary compliance and difficulty in having a real control group or blinding the interventions. In addition, these studies require a very long follow-up as well as a high economic cost that can be more difficult to finance if there is no financial support from public institutions. Due to all these limitations, there are few nutritional intervention studies that have carried out a long follow-up at the end of the intervention [11][12].

The first scientific evidence of the legacy effect in patients with diabetes comes from the DCCT and the UKPDS studies, in which an intensive glycaemic control compared to standard treatment resulted in a significant reduction in cardiovascular mortality, nonfatal myocardial infarction, stroke and nephropathy. These beneficial effects persisted for more than a decade after the intervention was finished [13][14]. Furthermore, the VADT trial provided the first evidence of the legacy effect in the reduction of a composite of major cardiovascular events (myocardial infarction, stroke, congestive heart failure or amputation for ischemic gangrene) in patients with poorly controlled and long duration type 2 diabetes mellitus (T2DM) after ten years of randomisation. Notwithstanding, these significant cardiovascular outcomes disappeared over a longer follow-up period (15 years) [15][16]. On the other hand, the ADVANCE and ACCORD trials, which included long-standing T2DM patients, showed no legacy effect in CVD. Differences observed among these trials may be explained due to the fact that the DCCT and UKPDS studies recruited younger patients with new-onset diabetes without known CVD, in contrast to the characteristics of the patients included in the ADVANCE and ACCORD studies [17][18].

Several clinical trials have analysed the legacy effect after tight blood pressure (BP) control with controversial results. On the one hand, the SHEP and the ROADMAP trials showed reductions in cardiovascular mortality, retinopathy and delayed onset of microalbuminuria, whereas the ASCOT study only demonstrated a small reduction in stroke mortality in the amlodipine-treatment group at the end of the entire follow-up [19][20][21]. On the contrary, the HDS and the ALLHAT studies did not provide clear evidence of a legacy effect, suggesting that this beneficial effect in patients with higher cardiovascular risk and probable subclinical CVD is unlikely to be achieved once in the post-trial phase, when BP is less strictly controlled. In addition, the benefits of antihypertensive treatment on major cardiovascular outcomes usually appear shortly after treatment implementation, and are attenuated when BP differences between groups are lost [22][23]. Therefore, based on clinical trials conducted, it appears that the legacy effect does not exist or seems to be mild and transient after tight antihypertensive regimens.

Different lipid-lowering trials, including ASCOT, WOSCOPS and ACCORD lipid studies, have also observed a legacy effect, resulting in a reduction in all-cause mortality and coronary heart disease mortality for 10–20 years after ending the interventional phase (statin or fibrates treatment), whereas the ALLHAT-LLT study did not provide evidence of a legacy effect after intensive lipid-lowering treatment [21][24][25][26]. It should be noted that in those trials in which a legacy effect was observed, the statin, a drug with pleiotropic effects, was compared against placebo. Moreover, the observation that five years of statin therapy led to a lower long-term risk of all-cause and CVD mortality raises the question of whether treatment with statins for 5–10 years would be sufficiently beneficial, while limiting lifetime exposure to the drug. However, there are still concerns about whether this therapeutic strategy could be effective in any patient, or in select populations only.

Until now, the legacy effect after multifactorial intervention has only been observed in the Steno-2 study, which included pharmacological and non-pharmacological measures. Indeed, lower mortality, CVD incidence and microvascular complications were detected in the intensive treatment arm of the trial compared to the standard treatment group. Surprisingly, the results were obtained in a sample of only 160 patients with intermediate cardiovascular risk but without CVD at baseline. It has been suggested that the positive long-term cardiovascular effects must be the result of a synergistic effect of the multifactorial intervention on cardiovascular risk factors [27]. Although these results are impressive, they have not been reproduced in subsequent studies.

The knowledge of pathophysiological mechanisms underlying the legacy effect adds plausibility to its existence. The best-known mechanisms are those related to the deleterious effects of hyperglycaemia through the development of metabolic memory induced during the first years of diabetes onset, which cannot be reversed with better glycaemic control. Thus, early interventions against hyperglycaemia could reduce reactive oxygen species production and oxidative stress in the mitochondria of endothelial cells, decrease advanced glycation end-product (AGE) formation and the expression of its receptor, and therefore, prevent activation of inflammatory processes and epigenetic changes in the arterial walls in the long term [4][5][28][29][30][31][32]. Likewise, dysregulation of renin-angiotensin system may be involved in vascular complication development, through increased oxidative stress and AGE formation. However, these mechanisms are not yet fully understood [33].

3. Conclusion

In conclusion, there is sufficient data to suggest the existence of a legacy effect after intensive intervention on cardiovascular risk factors in subjects with moderate-high vascular risk. However, this effect is not equivalent for all risk factors and could be influenced by patient characteristics, disease duration and the type of intervention performed. Currently, the available evidence suggests that the legacy effect would be greater in subjects with moderate-high cardiovascular risk but without known CVD, especially in patients with recent-onset diabetes. However, we should not withdraw any treatment to prevent CVD in these individuals as the level of available evidence on the legacy effect is low to moderate. Further investigation should be promoted to determine whether there is a legacy effect associated with nutritional interventions.


  1. Institute of Medicine (IOM). Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health; The National Academies Press: Washington, DC, USA, 2010; pp. 19–20, ISBN 978-0-309-14774-3.
  2. Parati, G.; Bilo, G.; Ochoa, J. Benefits of tight blood pressure control in diabetic patients with hypertension. Diabetes Care 2011, 34, S297–S303, doi:10.2337/dc11-s243.
  3. Khunti, K.; Kosiborod, M.; Ray, K. Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: Time to overcome multifactorial therapeutic inertia? Diabetes Obes Metab. 2018, 20, 1337–1341, doi:10.1111/dom.13243.
  4. Aschner, P.; Ruiz, A. Metabolic memory for vascular disease in diabetes. Diabetes Technol. Ther. 2012, 14, S68–S74, doi:10.1089/dia.2012.0012.
  5. Luna, P.; Guarner-Vfarías, J.; Hernández-Pacheco, G.; Martínez, M. Importance of metabolic memory in the development of vascular complications in diabetic patients. J. Cardiothorac. Vasc. Anesth. 2016, 30, 1369–1378, doi:10.1053/j.jvca.2016.02.008.
  6. Bianchi, C.; Miccoli, R.; Del Prato, S. Hyperglycemia and vascular metabolic memory: Truth or fiction? Curr. Diab. Rep. 2013, 13, 403–410, doi:10.1007/s11892-013-0371-2.
  7. Ceriello, A.; Inhat, M.; Thorpe, J. The “metabolic memory”: Is more than just tight glucose control necessary to prevent diabetic complications? J. Clin. Endocrinol. Metab. 2009, 94, 410–415, doi:10.1210/jc.2008-1824.
  8. De Cabo, R.; Mattson, MP. Effects of intermittent fasting on health, aging, and disease. N. Engl. J. Med. 2019, 381, 2541–2551, doi:10.1056/NEJMra1905136.
  9. Holme, I.; Retterstøl, K.; Norum, K.R.; Hjermann, I. Lifelong benefits on myocardial infarction mortality: 40-year follow-up of the randomized Oslo diet and antismoking study. J. Intern. Med. 2016, 280, 221–227, doi:10.1111/joim.12485.
  10. Estruch, R.; Ros, E.; Salas-Salvadó, J.; Covas, M.-I.; Corella, D.; Arós, F.; Gómez-Gracia, E.; Ruiz-Gutiérrez, V.; Fiol, M.; Lapetra, J.; et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 2018, 378, e34, doi:10.1056/NEJMoa1800389.
  11. Crichton, G.E.; Howe, P.R.; Buckley, J.D.; Coates, A.M.; Murphy, K.J.; Bryan, J. Long-term dietary intervention trials: Critical issues and challenges. Trials 2012, 13, 111, doi:10.1186/1745-6215-13-111.
  12. Staudacher, H.M.; Irving, P.M.; Lomer, M.C.E.; Whelan, K. The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. Proc. Nutr. Soc. 2017, 76, 203–212, doi:10.1017/S0029665117000350.
  13. Nathan, D.; Cleary, P.; Backlund, J.-Y.; Genuth, S.; Lachin, J.; Orchard, T.; Raskin, P.; Zinman, B. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 2005, 353, 2643–2653, doi:10.1056/NEJMoa052187.
  14. Holman, R.R.; Paul, S.K.; Bethel, M.A.; Matthews, D.R.; Neil, A.W. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 2008, 359, 1577–1589, doi:10.1056/NEJMoa0806470.
  15. Hayward, R.; Reaven, P.; Wiitala, W.; Bahn, G.; Reda, D.; Ge, L.; McCarren, M.; Duckworth, W.C.; Emanuele, N.V. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2015, 327, 2197–2206, doi:10.1056/NEJMoa1414266.
  16. Reaven, P.; Emamuele, N.; Wiitala, W.L.; Bahn, G.D.; Reda, D.J.; Mccarren, M.; Duckworth, W.C.; Hayward, R.A. Intensive glucose control in patients with type 2 diabetes—15-year follow-up. N. Engl. J. Med. 2019, 380, 2215–2224, doi:10.1056/NEJMoa1806802.
  17. Gerstein, H.; Beavers, D.P.; Bertoni, A.G.; Bigger, J.T.; Buse, J.B.; Craven, T.E.; Cushman, W.C.; Fonseca, V.; Geller, N.L.; Giddings, S.J.; et al. Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care 2016, 39, 701–708, doi:10.2337/dc15-2283.
  18. Zoungas, S.; Chalmers, J.; Neal, B.; Billot, L.; Li, Q.; Hirakawa, Y.; Arima, H.; Monaghan, H.; Joshi, R.; Colagiuri, S.; et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N. Engl. J. Med. 2014, 371, 1392–1406, doi:10.1056/NEJMoa1407963.
  19. Cushman, W.C.; Davis, B.R.; Pressel, S.L.; Cutler, J.A.; Einhorn, P.T.; Ford, C.E.; Oparil, S.; Probstfield, J.L.; Whelton, P.K.; Wright, J.T., Jr.; et al. Mortality and Morbidity During and After the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. J. Clin. Hypertens. 2012, 14, 20–31, doi:10.1111/j.1751-7176.2011.00568.x.
  20. Haller, H.; Ito, S.; Izzo, J.; Januszewicz, A.; Katayama, S.; Menne, J.; Mimran, A.; Rabelink, T.J.; Ritz, E.; Ruilope, L.M.; et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N. Engl. J. Med. 2011, 364, 907–917, doi:10.1056/nejmoa1007994.
  21. Nelson, M.R.; Chowdhury, E.K.; Doust, J.; Reid, C.M.; Wing, L.M.H. Ten-year legacy effects of baseline blood pressure “treatment naivety” in the Second Australian National Blood Pressure study. J. Hypertens. 2015, 33, 2331–2337, doi:10.1097/HJH.0000000000000709.
  22. Holman, R.; Bethel, M.; Neil, H.; Matthews, D. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N. Engl. J. Med. 2008, 359, 1565–1576, doi:10.1056/NEJMoa0806359.
  23. Kostis, J.B.; Cabrera, J.; Cheng, J.; Cosgrove, N.; Deng, Y.; Pressel, S.; Davis, B.R. Association between chlorthalidone treatment of systolic hypertension and long-term survival. JAMA 2011, 306, 2588–2593, doi:10.1001/jama.2011.1821.
  24. Furberg, C.D.; Wright, J.T.; Davis, B.R.; Cutler, J.A.; Alderman, M.; Black, H.; Cushman, E.; Grimm, R.; Haywood, L.J.; Leenen, F.; et al. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. Antihypertens. Lipid-Low. Treat. Prev. Heart Attack Trial 2002, 288, 2998–3007, doi:10.1001/jama.288.23.2998.
  25. Ford, I.; Murray, H.; McCowan, C.; Packard, C. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy. Circulation 2016, 133, 1073–1080, doi:10.1161/CIRCULATIONAHA.115.019014.
  26. Zhu, L.; Hayen, A.; Bell, K.J.L. Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: A secondary analysis of the ACCORDION study. Cardiovasc. Diabetol. 2020, 19, doi:10.1186/s12933-020-01002-x.
  27. Gæde, P.; Oellgaard, J.; Carstensen, B.; Rossing, P.; Lund-Andersen, H.; Parving, H.-H.; Pedersen, O. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016, 59, 2298–2307, doi:10.1007/s00125-016-4065-6.
  28. Yamagishi, S.; Nakamura, N.; Matsui, T. Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory. J. Diabetes 2017, 9, 141–148, doi:10.1111/1753-0407.12475.
  29. Berezin, A. Metabolic memory phenomenon in diabetes mellitus: Achieving and perspectives. Diabetes Metab. Syndr. Clin. Res. Rev. 2016, 10, S176–S183, doi:10.1016/j.dsx.2016.03.016.
  30. Testa, R.; Bonfigli, A.R.; Prattichizzo, F.; La Sala, L.; De Nigris, V.; Ceriello, A. The “metabolic memory” theory and the early treatment of hyperglycemia in prevention of diabetic complications. Nutrients 2017, 9, 437, doi:10.3390/nu9050437.
  31. Zhong, X.; Liao, Y.; Chen, L.; Liu, G.; Feng, Y.; Zeng, T.; Zhang, J. The MicroRNAs in the pathogenesis of metabolic memory. Endocrinology 2015, 156, 3157–3168, doi:10.1210/en.2015-1063.
  32. Reddy, M.; Zhang, E.; Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 2015, 58, 443–455, doi:10.1007/s00125-014-3462-y.
  33. Volpe, M.; Cosentino, F.; Tocci, G.; Palano, F.; Paneni, F. Antihypertensive therapy in diabetes: The legacy effect and RAAS blockade. Curr. Hypertens. Rep. 2011, 13, 318–324, doi:10.1007/s11906-011-0205-z.
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , ,
View Times: 1.1K
Revisions: 2 times (View History)
Update Date: 16 Nov 2020
Video Production Service