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][30]. 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][32]. 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][65]. 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][66,67].

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][35,37]. 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][42,43]. 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][40,62].

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][49,50,52]. 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][47,48]. 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]}[52,55,56,57]. 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][64]. 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]}[4,5,15,16,17,20,21]. 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][19].

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.