# The Legacy Effect and Metabolic Memory in Diabetes: A Comprehensive Review of Early Intensive Glycemic Control and Its Long-Term Impact on Microvascular and Macrovascular Outcomes

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### Background and Context

Diabetes mellitus represents one of the most consequential chronic disease burdens of the twenty-first century. According to the International Diabetes Federation, approximately 463 million people worldwide were living with diabetes in 2019, representing 9.3% of the global adult population aged 20–79 years, with projections indicating a rise to 578 million (10.2%) by 2030 and 700 million (10.9%) by 2045 (PMC10553000). By 2021, estimates had already reached 537 million, with projections to 783 million by 2045, and the economic burden of managing chronic complications is expected to exceed USD 1054 billion by that same year (PMC12730526, PMC12467019). The disease is not merely a metabolic inconvenience: it is a leading cause of blindness among the adult working-age population, the primary driver of chronic kidney disease and dialysis initiation, and the leading cause of non-traumatic lower-limb amputation, with more than 60% of such amputations occurring in people with diabetes (PMC12467019). Patients with diabetes carry a two- to four-fold excess risk of heart disease or stroke compared to people without diabetes and are more vulnerable to premature death (PMC12467019). Cardiovascular disease accounts for over 70% of deaths in type 2 diabetes patients (PMC10553000).

Against this backdrop, the central clinical question of how aggressively and how early to control blood glucose has occupied diabetes researchers and clinicians for more than four decades. The intuitive hypothesis — that normalizing blood glucose early in the disease course would prevent or delay the onset of vascular complications — was tested in landmark randomized controlled trials beginning in the 1980s and 1990s. What emerged from the long-term follow-up of these trials was a phenomenon that has since been termed the "legacy effect" or "metabolic memory": the observation that a period of intensive glycemic control, even if subsequently discontinued or matched by the comparator group, confers durable benefits on vascular outcomes that persist for years or even decades beyond the active intervention period (PMC8614708, PMC7690390). The term "legacy" in this context carries its etymological weight — it refers to what one generation of treatment passes to the next phase of a patient's life, something that remains from an earlier time of therapeutic effort (PMC8614708).

The concept of metabolic memory was first described in animal models before it was confirmed in human trials. In 1987, Engerman and colleagues observed that dogs in which good glycemic control was preceded by a longer period of abnormal glucose levels had a higher incidence of progression of diabetic retinopathy — a finding that suggested the vascular system retained a "memory" of prior hyperglycemic exposure that could not be fully erased by subsequent normalization of glucose (PMC7690390, PMC8614708). Subsequent in vitro work demonstrated long-term overexpression of fibronectin mRNA in the kidneys and hearts of streptozotocin-induced diabetic rats despite restoration of euglycemia, and the same phenomenon was observed in cultured endothelial cells exposed to high glucose concentrations — the increased expression of fibronectin and collagen IV persisted through subsequent cell passages even after glucose normalization (PMC8614708). These preclinical observations set the stage for the clinical legacy effect concept, which was formally established through the post-trial follow-up phases of the Diabetes Control and Complications Trial (DCCT/EDIC) in type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes — two of the most consequential trials in the history of endocrinology (PMC8614708, PMC7690390).

The clinical and public health importance of the legacy effect cannot be overstated. If early intensive glycemic control confers durable protection against microvascular and macrovascular complications that outlasts the period of active treatment, then the timing of intervention becomes as important as its intensity. This has profound implications for screening programs, treatment initiation thresholds, and the prioritization of resources in healthcare systems worldwide. Conversely, the corollary — that prolonged poor glycemic control imprints a lasting adverse "metabolic memory" that cannot be fully reversed by later improvements — argues urgently for early diagnosis and prompt treatment. The present review synthesizes the clinical trial evidence, mechanistic underpinnings, and unresolved controversies surrounding the legacy effect in both type 1 and type 2 diabetes, with particular attention to the differential impact on microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (cardiovascular events, stroke, mortality) endpoints across extended follow-up periods spanning decades.

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### Molecular and Mechanistic Pathways

#### Oxidative Stress and Mitochondrial Superoxide Overproduction

The foundational mechanistic hypothesis linking hyperglycemia to persistent vascular damage centers on the overproduction of mitochondrial reactive oxygen species (ROS). Chronic hyperglycemia induces uncoupling of the mitochondrial electron transfer chain in endothelial cells, causing excessive generation of superoxide anion and other ROS, and these oxidative stress markers can persist in endothelial cells despite glucose normalization after prolonged hyperglycemia (PMC7690390). The superoxide overproduction is not merely a transient response to acute hyperglycemia; it activates a cascade of downstream pathways that collectively sustain vascular inflammation and damage long after glucose levels have been corrected.

Superoxide anion inhibits GAPDH activity, leading to accumulation of glycolytic intermediates that react non-enzymatically with proteins, lipids, and nucleic acids to form advanced glycation end-products (AGEs) — stable, irreversible modifications that accumulate in long-lived proteins such as collagen and cannot be readily degraded by normal metabolic enzymes. AGEs promote oxidative stress, vascular hyperpermeability, pathological angiogenesis, and thrombogenic reactions via RAGE interaction, and continue to induce late diabetic complications even after blood glucose normalization — an effect explicitly termed the "legacy effect" in the mechanistic literature (PMC7690390, PMC10910816). In patients with diabetes, the detoxification system for methylglyoxal (MGO) — a highly reactive dicarbonyl compound primarily derived from glycolysis and a major precursor of AGEs — is impaired, leading to increased MGO concentrations and glycotoxic burden (PMC10910816).

Postprandial glucose oscillations in diabetic patients have been associated with increased ROS marker levels and vascular stress; the cells' inability to adapt to this dynamic environment leads to cell damage and elevated collagen and fibronectin levels that remain abnormal for several days after glucose levels have normalized (PMC7690390). Experimental evidence has demonstrated that transient hyperglycemia induces even more vascular damage than sustained hyperglycemia of equivalent magnitude, primarily mediated through oxidative stress (PMC7792304). The implication is that the pattern of glucose exposure, not just its average level, shapes the epigenetic and structural legacy that persists in vascular tissues.

#### Epigenetic Modifications: The Molecular Substrate of Memory

The most compelling mechanistic explanation for why vascular damage persists after glucose normalization lies in epigenetic reprogramming — heritable changes in gene expression that do not involve alterations in the DNA sequence itself but that can be transmitted through cell divisions and maintained over long periods. Several distinct epigenetic mechanisms have been identified in the context of hyperglycemia-induced metabolic memory (PMC8614708, PMC7690390, PMC10910816).

The most extensively characterized epigenetic mechanism involves histone lysine methylation. Hyperglycemia-dependent ROS production induces mono-methylation of histone 3 at lysine 4 (H3K4me1) by the methyltransferase Set7/9 at the proximal promoter region of the RELA gene (encoding the p65 subunit of NF-κB), resulting in upregulation of NF-κB and persistent vascular inflammation that persists even after glucose normalization (PMC8614708). In parallel, ROS production induces CpG hypomethylation and increased H3 histone acetylation in the p66Shc promoter region, leading to higher levels of p66Shc and significant activation of protein kinase C (PKC), thereby sustaining oxidative stress, endothelial dysfunction, and vascular damage in a self-reinforcing feed-forward loop (PMC8614708).

Epigenome profiling of white blood cells from patients in the DCCT trial showed an enrichment of histone acetylation marks at promoters of inflammatory genes in patients with progressive retinopathy and nephropathy compared to controls, and this epigenetic mark significantly correlated with the mean HbA1c during the trial (PMC8614708). This finding is particularly important because it links the clinical legacy effect observed in DCCT/EDIC directly to specific epigenetic signatures in circulating immune cells, providing a mechanistic bridge between the trial data and the molecular biology.

The concept of "trained immunity" extends the epigenetic memory framework to the context of hypercholesterolemia and atherosclerosis, which frequently co-occurs with diabetes. Oxidized LDL (oxLDL) primes monocytes and endothelial cells through enrichment of activating histone marks (H3K27ac and H3K4me3) at the promoters of inflammatory genes including ICAM-1, TNF-α, IL-6, and MCP-1, and upon subsequent stimulation these primed cells mount an exaggerated inflammatory response that is blocked by histone methyltransferase inhibitors (PMC8614708). This mechanism is relevant to the legacy effect in diabetes because hyperglycemia and dyslipidemia frequently coexist, and the epigenetic priming by both stimuli may converge on common inflammatory effectors in the vascular wall (PMC8614708).

In the context of glycemic variability specifically, Costantino and colleagues demonstrated that mean amplitude of glycemic excursions (MAGE) was independently associated with adverse epigenetic signatures on the p66Shc promoter and promoted chromatin changes, leading to persistent vascular dysfunction in patients with type 2 diabetes who had achieved target HbA1c levels (PMC7792304). This finding is mechanistically significant because it demonstrates that epigenetic damage can occur even in patients with apparently adequate mean glycemic control, if that control is achieved with high variability — a finding with direct implications for how we define and measure "good" glycemic control in clinical practice.

#### Advanced Glycation End-Products, the Polyol Pathway, and Hexosamine Flux

Beyond the epigenetic mechanisms, several classical biochemical pathways contribute to the metabolic memory phenomenon and to the persistence of vascular damage after glucose normalization. The polyol pathway, activated by intracellular glucose accumulation, converts glucose to sorbitol via aldose reductase and then to fructose via sorbitol dehydrogenase; this pathway has been implicated in the pathological processes leading to diabetic neuropathy and other vascular complications alongside the hexosamine pathway, protein kinase C pathway, and oxidative stress (PMC10553000). The hexosamine pathway, which diverts fructose-6-phosphate from glycolysis, has similarly been identified as a contributor to diabetic vascular pathology through its effects on protein modification and inflammatory signaling (PMC10553000).

The diacylglycerol (DAG)-protein kinase C (PKC) pathway is activated by hyperglycemia through increased de novo synthesis of DAG from glycolytic intermediates. PKC activation has multiple downstream consequences including increased expression of adhesion molecules, proinflammatory cytokines, and growth factors, as well as activation of NF-κB — the same transcription factor targeted by the histone methylation mechanism described above (PMC7690390). The convergence of multiple hyperglycemia-activated pathways on NF-κB provides a mechanistic explanation for why the inflammatory and vascular consequences of hyperglycemia are so difficult to reverse: even if one pathway is normalized, others may continue to drive NF-κB activation and its downstream consequences.

The interaction between these pathways and the epigenetic mechanisms creates a self-sustaining cycle that is the molecular basis of metabolic memory. Hyperglycemia activates the polyol, hexosamine, PKC, and AGE/RAGE pathways, which collectively generate ROS and activate NF-κB. The resulting inflammatory signaling induces epigenetic modifications (histone methylation, histone acetylation, CpG methylation changes) that sustain NF-κB activity and inflammatory gene expression even after glucose normalization. The AGEs that accumulate in the extracellular matrix continue to signal through RAGE, maintaining the inflammatory milieu. And the epigenetic changes, being heritable through cell division, ensure that daughter cells of vascular endothelial cells, smooth muscle cells, and immune cells carry the same pro-inflammatory epigenetic program — perpetuating the legacy of prior hyperglycemia across cellular generations (PMC8614708, PMC7690390, PMC10910816).

#### Glycemic Variability as an Independent Contributor to Metabolic Memory

An emerging and mechanistically important dimension of the metabolic memory concept is the role of glycemic variability — fluctuations in blood glucose levels — as a contributor to vascular damage that is independent of mean glucose levels. The biological plausibility of this contribution rests on the observation that transient hyperglycemia induces greater vascular damage than sustained hyperglycemia of equivalent magnitude, primarily through oxidative stress mechanisms (PMC7792304). Short-term glycemic fluctuations induce superoxide overproduction, inflammatory cytokine generation, increased oxidative stress, and endothelial dysfunction and damage — all of which contribute to chronic diabetic complications (PMC7792304, PMC6389075).

The epigenetic dimension of glycemic variability-induced damage has been directly demonstrated: MAGE was independently associated with adverse epigenetic signatures on the p66Shc promoter in patients with type 2 diabetes, even those with target HbA1c levels (PMC7792304). This finding suggests that glycemic variability can imprint epigenetic damage that contributes to the metabolic memory independently of the mean glucose level captured by HbA1c. The clinical implication is that HbA1c alone may be an insufficient metric for assessing the risk of metabolic memory and its vascular consequences — a point that has significant implications for how we design and evaluate glycemic control interventions in the context of the legacy effect.

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### Clinical Evidence and Implications

#### The DCCT/EDIC Study: Establishing the Legacy Effect in Type 1 Diabetes

The Diabetes Control and Complications Trial (DCCT) was a landmark randomized controlled trial that enrolled 1,441 patients with type 1 diabetes and compared intensive glycemic control (targeting near-normal blood glucose) with conventional therapy. After more than 6 years of intervention, the development of microvascular complications was significantly diminished in the intensive treatment group: severe retinopathy was reduced by 53%, clinical neuropathy by 40%, and microalbuminuria by 61% (PMC8614708). The intensive treatment group also showed significantly lower rates of severe proliferative or non-proliferative retinopathy (HR 0.47, 95% CI 0.14–0.67), clinical neuropathy (HR 0.60, 95% CI 0.38–0.74), and microalbuminuria (HR 0.39, 95% CI 0.21–0.52) compared to the conventional group (PMC7690390). These findings established beyond reasonable doubt that intensive glycemic control could prevent or delay microvascular complications in type 1 diabetes.

The legacy effect was revealed in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study, which followed the DCCT cohort for an additional 17 years after the trial ended. As reported in the EDIC follow-up, within approximately one year of the DCCT trial's conclusion, HbA1c levels in the two groups converged — the formerly intensive group's HbA1c rose to approximately 7.9% and the conventional group's fell to approximately 7.8% — and remained similar throughout the subsequent follow-up period (PMC8614708). Despite this convergence in glycemic control, the former intensive therapy group continued to experience significantly lower rates of complications. Despite HbA1c convergence, the former intensive therapy group in DCCT/EDIC had a 57% reduction in the incidence of cardiovascular events (nonfatal myocardial infarction, stroke, or death from cardiovascular disease; HR 0.43, 95% CI 0.12–0.79) and a 46% lower incidence of nephropathy (HR 0.54, 95% CI 0.34–0.84) during the 17-year EDIC follow-up (PMC8614708, PMC7690390).

These findings from DCCT/EDIC are remarkable for several reasons. First, the cardiovascular benefit emerged during the post-trial follow-up period, not during the active trial itself — during the DCCT, there was no significant difference in cardiovascular events between the groups, likely because the trial was too short and the participants too young for cardiovascular events to accumulate. The macrovascular legacy effect thus required a decade or more to become manifest, a temporal pattern that has important implications for the design of clinical trials and the interpretation of shorter-term studies. Second, the magnitude of the cardiovascular benefit (57% reduction) is comparable to or exceeds the benefits seen with statins or antihypertensive therapy in high-risk populations, suggesting that early glycemic control in type 1 diabetes is one of the most powerful cardiovascular preventive interventions available. Third, the persistence of benefit despite convergence of HbA1c levels provides the clearest possible demonstration that the legacy effect is a real biological phenomenon, not merely a reflection of ongoing differences in glycemic control.

#### The UKPDS and Its Post-Trial Follow-Up: Legacy Effect in Type 2 Diabetes

The United Kingdom Prospective Diabetes Study (UKPDS) was the definitive trial of intensive glycemic control in newly diagnosed type 2 diabetes. The study recruited patients with newly diagnosed type 2 diabetes; after a three-month dietary run-in period, they were randomized to intensive glucose-lowering treatment (sulfonylurea, insulin, or metformin) or to conventional dietary management, and were followed for ten years. Intensive glucose management was associated with a significant reduction for any diabetes-related endpoint and for any diabetes-related death compared to the control group, with most of the risk reduction in the composite endpoint attributable to a 25% risk reduction in microvascular endpoints (PMC7690390). However, there was no significant reduction in macrovascular endpoints (myocardial infarction, stroke) during the active trial period — a finding that initially suggested that glycemic control might not protect against cardiovascular disease in type 2 diabetes (PMC8614708, PMC7690390).

During the active UKPDS trial period, intensive therapy was associated with a 12% reduction in any diabetes-related endpoint (p<0.05), a 25% reduction in microvascular endpoints (primarily retinopathy), but no significant reduction in macrovascular endpoints (myocardial infarction, stroke) (PMC8614708, PMC7690390).

The post-trial follow-up of the UKPDS cohort, conducted for an additional 10 years after the trial ended, revealed the legacy effect in type 2 diabetes with striking clarity. As in DCCT/EDIC, HbA1c differences between the groups disappeared within one year of the trial's conclusion. The UKPDS post-trial follow-up (10 years after trial end, despite HbA1c convergence within one year) showed significant risk reductions in the former intensive therapy group: any diabetes-related endpoint reduced by 9% (RR 0.91, 95% CI 0.83–0.99), microvascular disease by 24% (RR 0.76, 95% CI 0.64–0.89), myocardial infarction by 15% (RR 0.85, 95% CI 0.74–0.97), and death from any cause by 13% (RR 0.87, 95% CI 0.79–0.96) (PMC8614708, PMC7690390). The emergence of a significant macrovascular benefit — specifically the reduction in myocardial infarction — during the post-trial follow-up, when it had not been present during the active trial, is the defining demonstration of the legacy effect for macrovascular outcomes in type 2 diabetes.

In the UKPDS metformin subgroup, overweight patients randomized to metformin-based intensive therapy showed legacy benefits of a 21% reduction in any diabetes-related endpoint (RR 0.79, 95% CI 0.66–0.95), a 33% reduction in myocardial infarction (RR 0.67, 95% CI 0.51–0.89), and a 27% reduction in death from any cause (RR 0.73, 95% CI 0.59–0.89) during post-trial follow-up (PMC7690390). These findings suggest that the choice of glucose-lowering agent may modulate the magnitude of the legacy effect, with metformin potentially conferring additional vascular protection beyond its glucose-lowering action — a hypothesis consistent with metformin's known pleiotropic effects on endothelial function, lipid profiles, and inflammation (PMC10910816).

The UKPDS also included a blood pressure arm, in which newly diagnosed type 2 diabetic patients with hypertension were randomized to tight versus less-tight blood pressure control. In the UKPDS blood pressure arm, tight blood pressure control significantly reduced cardiovascular endpoints during the active trial, but the blood pressure legacy effect was largely absent in post-trial follow-up, with the exception of a persistent reduction in peripheral vascular disease (RR 0.50, 95% CI 0.28–0.92) (PMC7690390). This differential legacy effect — robust for glycemic control but attenuated for blood pressure control — suggests that the biological mechanisms underlying metabolic memory are specific to hyperglycemia-induced epigenetic and structural changes, rather than being a generic consequence of any cardiovascular risk factor reduction.

#### The ACCORD, ADVANCE, and VADT Trials: When the Legacy Effect Fails to Materialize

The apparent success of the DCCT/EDIC and UKPDS in demonstrating a legacy effect led to the design of three large trials in the 2000s that attempted to extend intensive glycemic control to patients with longer-standing type 2 diabetes and higher cardiovascular risk: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, and the Veterans Affairs Diabetes Trial (VADT). The results of these trials were sobering and have generated ongoing controversy about the conditions under which the legacy effect can be expected to occur.

The ACCORD trial enrolled more than 10,000 long-lasting type 2 diabetic patients. The trial was stopped prematurely after a median follow-up of 3.5 years due to a 35% increase in cardiovascular mortality in the intensive therapy group (HR 1.35, 95% CI 1.04–1.76), along with a significantly higher incidence of severe hypoglycemia and weight gain (PMC10383300). As reported in the legacy effect literature, long-term follow-up of the ACCORD cohort did not reveal any long-term benefit of the intensive intervention period (PMC8614708).

The ADVANCE trial enrolled 11,140 patients with type 2 diabetes aged ≥55 years with at least one additional cardiovascular risk factor, randomized to intensive glucose-lowering treatment (targeting HbA1c <6.5%) or standard control, alongside a blood pressure intervention arm (perindopril-indapamide versus placebo), and followed for five years (PMC7690390). During the intervention phase, intensive glucose control produced a significant reduction in microvascular events (14%), primarily due to a reduction in nephropathy incidence, with no significant increase in cardiovascular mortality (PMC7690390). The six-year post-trial follow-up found a significant reduction in all-cause mortality (HR 0.91, 95% CI 0.84–0.99) and cardiovascular mortality (HR 0.88, 95% CI 0.77–0.99) in those patients originally treated with perindopril-indapamide compared to placebo, but intensive glucose control did not provide any long-term benefits during the post-trial follow-up (PMC7690390).

The VADT enrolled 1,791 patients with poorly controlled long-standing type 2 diabetes (mean duration 11.5 years), 40% of whom had already suffered a cardiovascular event. They were randomly assigned to intensive or standard therapy for a median of 5.6 years. The intensive glucose-lowering treatment led to a between-group difference of 1.5 percentage points in HbA1c levels (6.9% in the intensive-therapy group vs. 8.4% in the standard-therapy group) during the in-trial period. At 10 years of follow-up, a significantly lower incidence of cardiovascular disease was observed in the former intensive therapy group (HR 0.83, 95% CI 0.70–0.99), but this benefit disappeared at 15 years (HR 0.91, 95% CI 0.78–1.06; all-cause mortality HR 1.02, 95% CI 0.88–1.18) (PMC7690390). The VADT thus provides evidence for a modest and transient legacy effect in patients with long-standing, poorly controlled type 2 diabetes — a benefit that emerged later than in the UKPDS but was ultimately not sustained.

#### The Steno-2 Study: Multifactorial Intervention and the Most Dramatic Legacy Effect

While the DCCT/EDIC and UKPDS focused on glycemic control in isolation, the Steno-2 study examined the legacy effect of intensive multifactorial intervention — simultaneously targeting glycemia, blood pressure, lipids, and microalbuminuria. The Steno-2 clinical trial enrolled 160 patients with type 2 diabetes and microalbuminuria, randomly assigned to either conventional treatment or intensive treatment, which included behavior modification and pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of CVD with aspirin. After a mean follow-up of 7.8 years, the intensive-treatment group had significantly greater reductions in glycated hemoglobin values, blood pressure, serum cholesterol and triglyceride levels, and urinary albumin excretion rate than the conventional-treatment group, resulting in a 50% reduction in the risk of cardiovascular and microvascular events (PMC10553000). The Steno-2 post-trial follow-up extending to 21 years from randomization revealed a 45% reduction in all-cause mortality, a 62% reduction in cardiovascular mortality, a 48% reduction in macroalbuminuria, a 33% reduction in retinopathy progression, and a 41% reduction in autonomic neuropathy in the intensive treatment arm, with death and first cardiovascular event delayed by approximately 7.9 and 8.0 years, respectively (PMC7690390).

The Steno-2 results are remarkable not only for their magnitude but for their context: this was a small trial (n=160) with intermediate cardiovascular risk patients who did not have established cardiovascular disease at baseline. The fact that such a small study produced such dramatic and durable results — with a legacy effect that persisted for more than a decade after the active intervention — suggests that the timing of multifactorial intervention (before cardiovascular disease is established) and the comprehensiveness of the intervention (targeting multiple risk factors simultaneously) are critical determinants of the legacy effect's magnitude and durability (PMC7690390).

#### Real-World and Observational Evidence Supporting the Legacy Effect

Beyond the landmark RCTs, several observational and real-world studies have provided supporting evidence for the legacy effect concept. The Fremantle Diabetes Study, the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), and the Diabetes and Aging Study (DAS) have all reinforced the legacy effect theory in real-world diabetes care settings (PMC8614708).

The ADDITION study found that population-based diabetes screening was associated with a significant 21% lower risk of all-cause mortality (HR 0.79, 95% CI 0.74–0.84) and a significant 16% lower risk of cardiovascular events (HR 0.84, 95% CI 0.80–0.89) at 10-year follow-up compared to unscreened patients, and was associated with less need for insulin therapy and slightly better long-term glycemic control (PMC7690390). These findings suggest that earlier diagnosis itself, by enabling earlier intervention, contributes to the legacy effect.

The Diabetes and Aging Study found that HbA1c ≥6.5% in the first year after type 2 diabetes diagnosis was associated with higher risk of micro- and macrovascular events, while HbA1c ≥8% in the first year after diagnosis was associated with significantly higher mortality risk (PMC7690390). These results suggest that achieving near-normoglycemia in the first 12 months after type 2 diabetes diagnosis is necessary to generate a legacy effect — a finding that aligns with the mechanistic hypothesis that epigenetic damage accumulates rapidly in the early hyperglycemic period and that early intervention can prevent this damage from becoming irreversible.

#### Microvascular Legacy Effects: Retinopathy, Nephropathy, and Neuropathy

The legacy effect for microvascular complications is the most consistently demonstrated across trials and populations. In DCCT/EDIC, the reductions in retinopathy (53%), neuropathy (40%), and microalbuminuria (61%) achieved during the active trial period were maintained and extended during the 17-year post-trial follow-up, even as HbA1c levels converged between groups (PMC8614708). In the UKPDS, the 25% reduction in microvascular endpoints during the active trial persisted as a 24% reduction in microvascular disease during the 10-year post-trial follow-up (PMC8614708, PMC7690390).

For diabetic retinopathy specifically, the relationship between glycemic control and the legacy effect is nuanced. A pooled analysis of 35 global studies found an overall prevalence of diabetic retinopathy of 34.6% (95% CI 34.5–34.8) among people with diabetes, with proliferative retinopathy affecting 6.96% and vision-threatening retinopathy affecting 10.2% (PMC10553000). In the UKPDS, each 1% reduction in updated mean HbA1c was associated with a 37% reduction in risk for microvascular complications, predominantly retinopathy (95% CI 33–41%, p<0.001) (PMC10553000). The Rio de Janeiro Type 2 Diabetes Cohort Study, with a median follow-up of 9.3 years, found that 24-month HbA1c variability predicted retinopathy incidence or worsening specifically in patients with good glycemic control (mean HbA1c ≤7.5%), with HRs of 1.88 (95% CI 1.03–3.43) for HbA1c-SD, and that 24-month fasting glucose variability (FG-SD) independently predicted new microalbuminuria development (HR 1.34, 95% CI 1.00–1.79) and renal failure (HR 1.37, 95% CI 1.08–1.74) per 1-SD increment (PMC6389075). This finding suggests that in patients who have achieved adequate mean glycemic control, glycemic variability becomes the dominant driver of retinopathy risk — a mechanistically coherent observation given the role of glucose oscillations in oxidative stress and epigenetic damage.

For diabetic nephropathy, the legacy effect is similarly robust. The ROADMAP trial, which randomized patients with type 2 diabetes to olmesartan or placebo for 3.2 years, showed that during the 6.5-year observational follow-up, congestive heart failure requiring hospitalization was significantly lower (OR 0.23, 95% CI 0.06–0.85) and diabetic retinopathy was significantly lower (OR 0.34, 95% CI 0.15–0.78) in the former olmesartan group (PMC7690390). The Rio de Janeiro cohort study found that HbA1c variability (HbA1c-SD) was an independent predictor of new-incident peripheral neuropathy (OR 1.82, 95% CI 1.20–2.75) in fully adjusted models, while mean HbA1c was the main predictor of neuropathy worsening rather than new incidence (PMC6389075). This differential relationship — variability predicting new neuropathy, mean HbA1c predicting progression — suggests that the initial development of neuropathy may be more sensitive to glycemic fluctuations, while its progression is driven more by sustained hyperglycemia.

#### Macrovascular Legacy Effects: Cardiovascular Events and Mortality

The macrovascular legacy effect is more variable across trials and appears to be critically dependent on the timing of intervention relative to disease duration and the presence of pre-existing cardiovascular disease. The clearest evidence comes from DCCT/EDIC (57% reduction in cardiovascular events, HR 0.43, 95% CI 0.12–0.79) and the UKPDS post-trial follow-up (15% reduction in myocardial infarction, RR 0.85, 95% CI 0.74–0.97; 13% reduction in all-cause mortality, RR 0.87, 95% CI 0.79–0.96) — both studies that enrolled patients with newly diagnosed or early-stage diabetes without established cardiovascular disease (PMC8614708, PMC7690390).

A systematic review examining the impact of intensive glycemic treatment on macrovascular outcomes pooled five major RCTs (UKPDS, ADVANCE, ACCORD, VADT, and PROactive) including a total of 32,649 patients, of whom 17,267 received intensive glycemic control therapy (PMC10383300). The pooled analysis found a significant reduction in non-fatal myocardial infarction in the intensive treatment groups, but no significant reduction in non-fatal stroke (5.3% vs. 5.1%, p=0.69 in a meta-analysis of nine RCTs with 12,497 patients) and no significant reduction in cardiovascular mortality when the five trials were combined (PMC10383300). The ACCORD trial's finding of a 35% increase in cardiovascular mortality with intensive therapy (HR 1.35, 95% CI 1.04–1.76) was the dominant driver of the null or negative result for cardiovascular mortality in the pooled analysis (PMC10383300).

Regarding blood pressure-lowering legacy effects, the SHEP trial enrolled elderly patients with isolated systolic hypertension who were randomized to chlorthalidone therapy or placebo. After a 22-year follow-up, significant albeit modest life expectancy gains free from cardiovascular-related death were observed in the chlorthalidone group, corresponding to approximately one day of life gained for each month of treatment (HR 0.89, 95% CI 0.80–0.99) (PMC7690390). This finding illustrates that legacy effects from antihypertensive therapy, while present in specific populations, may be more modest and population-dependent than those observed with early intensive glycemic control in newly diagnosed diabetes.

For lipid-lowering therapy, the WOSCOPS 20-year follow-up demonstrated a sustained beneficial effect of pravastatin, with a significant reduction in all-cause mortality (HR 0.87, 95% CI 0.80–0.94) attributable mainly to a 21% decrease in cardiovascular death (HR 0.79, 95% CI 0.69–0.90) — a legacy effect that persisted more than 15 years after the active trial ended (PMC7690390). The ASCOT-LLA 16-year follow-up after initial randomization showed a significant risk reduction in cardiovascular mortality (HR 0.85, 95% CI 0.72–0.99) in those assigned to atorvastatin, though no differences in all-cause mortality or stroke were seen between the atorvastatin and placebo groups during the post-trial study period (PMC7690390). A meta-analysis of eight statin trials found evidence of a legacy effect on all-cause mortality, with a subgroup analysis of three primary prevention trials demonstrating legacy effects on cardiovascular mortality (by 13%) and all-cause mortality (by 10%) (PMC7690390).

#### The Role of Early Intensive Insulin Therapy in Establishing Glycemic Legacy

An emulated target trial using real-world electronic health record data from three major South Korean tertiary hospitals (n=2,092 newly diagnosed type 2 diabetes patients achieving HbA1c <7.0% after initial intensive therapy, 355 patients per group after 1:1 propensity score matching) found that initial intensive insulin therapy (IIT) was associated with a significantly lower risk of glycemic remission failure (adjusted HR 0.41, 95% CI 0.31–0.73) compared to combination oral antidiabetic drugs (COAD), with mean HbA1c remaining below 7.0% even at 3 years post-treatment in the IIT group (PMC12863771). The authors explicitly invoke the concept of metabolic memory to explain these findings, noting that early glycemic normalization through IIT may facilitate recovery of β-cell function and establish a more durable glycemic legacy (PMC12863771). This study provides real-world evidence that the choice of initial intensive therapy modality — not just the achievement of glycemic targets — may influence the durability of the glycemic legacy.

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### Safety Profile and Adverse Events

#### Hypoglycemia: The Critical Counterweight to Intensive Therapy

The most important safety concern associated with intensive glycemic control — and the one most directly relevant to the legacy effect — is hypoglycemia. The ACCORD trial's finding of increased cardiovascular mortality in the intensive therapy group has been attributed in part to the significantly higher incidence of severe hypoglycemia in that group, along with weight gain (PMC10383300, PMC8614708). Hypoglycemia requiring assistance was significantly more frequent in the intensive therapy groups across ACCORD, ADVANCE, and VADT, and these trials all showed no significant difference in the incidence of macrovascular complications or cardiovascular mortality between intensive and standard treatment groups, but a higher incidence of severe hypoglycemia in the intensive group (PMC10553000). The potential mechanisms by which hypoglycemia could increase cardiovascular risk include release of inflammatory cytokines, increased platelet activation, endothelial dysfunction, and cardiac arrhythmias (PMC7792304).

The damage associated with severe hypoglycemia may outweigh the possible advantage of intensive blood glucose reduction treatment, particularly in patients with long-standing diabetes, established cardiovascular disease, or impaired hypoglycemia awareness (PMC10383300). A meta-analysis examining the benefit/risk profile of intensive hypoglycemic treatment found that a 9% decrease or a 19% increase in all-cause mortality and a 14% decrease or a 43% increase in cardiovascular deaths could not be ruled out — a range of uncertainty that underscores the importance of individualized glycemic targets (PMC10383300). The implication for the legacy effect is that the conditions under which intensive therapy is applied matter enormously: the same degree of HbA1c reduction that confers a legacy benefit in a newly diagnosed patient without cardiovascular disease may cause net harm in a patient with long-standing diabetes and established cardiovascular disease.

#### Treatment-Induced Diabetic Neuropathy

A less widely recognized but clinically important adverse effect of rapid intensive glycemic control is treatment-induced diabetic neuropathy (TIDN) — the abrupt appearance of intense neuropathic pain in the context of improved glycemic regulation. The concept was first described in 1933 as "insulin neuritis" and has been more systematically characterized in recent decades (PMC10383300). In a 5-year review of 954 patients evaluated for TIDN at two registered sites in a single medical center, 104 patients (10.9%) met diagnostic criteria for TIDN. Diagnostic criteria required onset of neuropathic pain or autonomic dysfunction within 8 weeks of a decrease in mean blood glucose, neuropathic pain of at least 3 points on a 10-point Likert scale or severe autonomic dysfunction, and a decrease in HbA1c of at least 2 percentage points over 3 months (PMC10383300).

A reduction in HbA1c exceeding 5% over a 6-month period was associated with a relative risk of TIDN exceeding 35%, with presentation of disseminated symptoms over the patient's entire body (PMC10383300). The pathophysiology of TIDN is not fully understood but may involve the onset of "relative" hypoglycemia in an individual with chronic high glucose levels, leading to a breakdown of energy-dependent axonal trafficking, or the generation of arteriovenous shunts leading to endoneural ischemia and regenerative nerve fiber discharge (PMC10383300). Importantly, TIDN is associated with concomitant development of other microvascular complications: before HbA1c reduction, less than half of the TIDN group had retinopathy and only 3% had proliferative retinopathy; after developing TIDN, 90% of the group had severe non-proliferative or proliferative retinopathy (PMC10383300). Microalbuminuria was detected in 17% of cases before TIDN development, but in 84% of individuals one year after TIDN onset (PMC10383300).

#### Early Worsening of Diabetic Retinopathy

In the initial DCCT study, an early progression of retinopathy occurred in 22% of the intensive treatment group compared to only 13% in the standard treatment group (PMC10383300). This early worsening — characterized by more cotton wool spots, intraretinal microvascular abnormalities, and/or diabetic macular edema — is paradoxical in the context of the long-term legacy benefit of intensive therapy for retinopathy. Rapid glycemic improvement may worsen diabetic retinopathy, and the extent of HbA1c lowering has been positively related to the risk of retinopathy advancement in multiple studies (PMC10383300). Similar concerns have been raised regarding the rapid HbA1c reduction observed with semaglutide in the SUSTAIN-6 trial, where five cases of blindness occurred in the semaglutide arm versus one in the placebo arm — an effect attributed to the magnitude and speed of HbA1c lowering rather than to semaglutide itself (PMC10383300).

#### Charcot's Neuroarthropathy and Renal Dysfunction

Two additional adverse effects associated with rapid intensive glycemic control have been described in smaller cohorts. Charcot's neuroarthropathy (CN) — a devastating complication of the joints — has been described in situations resembling intensive correction of hyperglycemia, including simultaneous kidney-pancreas transplantation. In two retrospective cohorts examining Charcot's neuroarthropathy (CN), a significant reduction in HbA1c levels occurred 3 and 6 months prior to the discovery of CN, and the high rate of CN after simultaneous pancreas-kidney transplantations reinforced the idea that rapid HbA1c reduction plays a key role in CN onset, proposed to involve inhibition of osteoprotegerin leading to increased RANKL levels (PMC10383300). For renal dysfunction, microalbuminuria was detected in 84% of TIDN patients one year after onset, and a small group (8%) with TIDN had a significant increase in serum creatinine requiring hemodialysis in some cases (PMC10383300). These findings suggest that the rapid correction of chronic hyperglycemia can paradoxically accelerate microvascular damage in the short term, even as it confers long-term protection — a temporal paradox that has important implications for the clinical management of patients transitioning from poor to intensive glycemic control.

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### Unresolved Controversies and Disagreements

#### Why Did ACCORD, ADVANCE, and VADT Fail to Show a Legacy Effect?

The most fundamental unresolved controversy in the legacy effect literature is why the DCCT/EDIC and UKPDS demonstrated robust and durable legacy benefits while ACCORD, ADVANCE, and VADT did not. Several explanatory hypotheses have been proposed, and the evidence supports a combination of factors rather than any single explanation (PMC8614708, PMC7690390, PMC10383300).

The most widely accepted explanation is the timing of intervention relative to disease duration and the presence of pre-existing cardiovascular disease. The DCCT enrolled patients with type 1 diabetes who were relatively young and had no established cardiovascular disease; the UKPDS enrolled patients with newly diagnosed type 2 diabetes. In contrast, ACCORD enrolled patients with a median diabetes duration of 10 years and either established cardiovascular disease or multiple cardiovascular risk factors; VADT enrolled patients with a mean diabetes duration of 11.5 years, 40% of whom had already suffered a cardiovascular event; and ADVANCE enrolled patients with a mean diabetes duration of 8 years (PMC8614708, PMC7690390). The mechanistic interpretation is that by the time patients in ACCORD, ADVANCE, and VADT were enrolled, the epigenetic damage from years of hyperglycemia had already been imprinted in vascular tissues, and the window for preventing this damage through glycemic control had closed. The "sooner the better" principle — that interventions on glycemic control need to be implemented early in the disease, certainly before any cardiovascular event, perhaps even within the first year — has emerged as the central clinical lesson from this comparison (PMC8614708).

A second explanatory factor is the aggressiveness and rapidity of glycemic control in ACCORD. The ACCORD trial targeted HbA1c <6.0% — a level of near-normoglycemia that required aggressive multi-drug regimens and was associated with significantly higher rates of severe hypoglycemia and weight gain. The increased cardiovascular mortality in ACCORD may have been driven by these adverse effects of the treatment rather than by the glycemic target itself (PMC10383300). The ACCORD trial's aggressive approach — using four to five glucose-lowering drugs simultaneously — may have introduced cardiovascular risks through hypoglycemia-induced arrhythmias, sympathoadrenal activation, and weight gain-related atherosclerosis that outweighed any potential benefit of glycemic control (PMC10383300). This interpretation is supported by the observation that the positive effect of glucose control on macrovascular outcomes in UKPDS and DCCT/EDIC became significant only after 10 years of follow-up — a duration that was not achieved in ACCORD, ADVANCE, or VADT (PMC10383300).

#### The Role of Glycemic Variability Versus Mean HbA1c

A second major controversy concerns whether mean HbA1c or glycemic variability is the more important determinant of vascular outcomes and the legacy effect. The traditional view, supported by the DCCT, UKPDS, and their post-trial follow-ups, is that mean HbA1c is the primary driver of microvascular and macrovascular complications. However, a growing body of evidence from observational studies and mechanistic research suggests that glycemic variability contributes independently to vascular damage, and may in some contexts be a more important predictor than mean HbA1c (PMC7792304, PMC6389075, PMC11853042).

The Rio de Janeiro Type 2 Diabetes Cohort Study (n=654, median follow-up 9.3 years) found that 24-month visit-to-visit glycemic variability parameters were better risk predictors than mean HbA1c levels for all micro- and macrovascular outcomes except retinopathy development/progression in poorly controlled patients and peripheral neuropathy progression (PMC6389075). Specifically, mean HbA1c was not an independent predictor of any macrovascular or mortality outcome in fully adjusted models, while FG-SD independently predicted total cardiovascular events (HR 1.36, 95% CI 1.09–1.69), cardiovascular mortality (HR 1.50, 95% CI 1.10–2.03), and all-cause mortality (HR 1.59, 95% CI 1.32–1.93) per 1-SD increment (PMC6389075). These findings directly challenge the primacy of mean HbA1c as the target for glycemic management.

However, this view is not universally accepted. The DCCT demonstrated that within-day glycemic variability, as determined from quarterly glucose profiles, did not participate in the development of microvascular complications — directly contradicting the hypothesis that short-term glycemic variability is an independent driver of microvascular damage (PMC7792304). The discrepancy between the DCCT finding and the observational cohort data may reflect differences in the populations studied (type 1 vs. type 2 diabetes), the metrics used to assess variability (within-day CGM-derived metrics vs. visit-to-visit HbA1c or fasting glucose variability), and the confounding effects of mean glucose levels on variability measures. The controversy remains unresolved, and the optimal metric for assessing glycemic control in the context of the legacy effect — whether HbA1c, glycemic variability, time in range, or some combination — is an active area of investigation.

#### The Adverse Legacy Effect: Metabolic Memory of Poor Control

A corollary of the legacy effect concept that has received less attention but is equally important is the adverse legacy effect — the persistent harm caused by a period of poor glycemic control that cannot be fully reversed by subsequent improvement. This concept is directly implied by the mechanistic framework of metabolic memory: if epigenetic damage accumulates during hyperglycemia and persists after glucose normalization, then patients who have experienced prolonged poor control carry a lasting vascular risk burden that exceeds what their current HbA1c would predict (PMC8614708, PMC10910816).

The failure of ACCORD, ADVANCE, and VADT to show legacy benefits — and the increased mortality in ACCORD — can be interpreted as evidence of an adverse legacy effect: the years of poor glycemic control before trial enrollment had already imprinted irreversible epigenetic and structural damage in the vascular system, and the subsequent intensive therapy could not overcome this damage and may have added additional harm through hypoglycemia and weight gain (PMC8614708). The Diabetes and Aging Study's finding that HbA1c ≥8% in the first year after diagnosis was associated with significantly higher mortality risk — even after subsequent improvement — provides direct observational evidence for the adverse legacy effect in type 2 diabetes (PMC7690390). The implication is that the window for establishing a beneficial legacy effect may be narrow, and that prolonged poor control before intervention may not only fail to benefit from subsequent intensive therapy but may actively worsen outcomes through the adverse metabolic memory it has established.

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### Limitations of the Evidence Base

The evidence base for the legacy effect in diabetes is subject to several important methodological limitations that constrain the strength of conclusions that can be drawn.

The most fundamental limitation is that the definitive evidence for the legacy effect comes from only two landmark trials — DCCT/EDIC and UKPDS — and their post-trial follow-up phases. Both of these studies were conducted in specific populations (type 1 diabetes and newly diagnosed type 2 diabetes, respectively) that may not be representative of the broader diabetes population seen in clinical practice. The generalizability of the legacy effect to patients with longer disease duration, established cardiovascular disease, or different ethnic backgrounds is uncertain and is directly contradicted by the ACCORD, ADVANCE, and VADT results.

The post-trial follow-up phases of DCCT/EDIC and UKPDS were observational rather than randomized, meaning that patients in both groups were free to receive any treatment after the trial ended. The convergence of HbA1c levels between groups during follow-up is consistent with the legacy effect interpretation, but it is also possible that unmeasured differences in treatment, lifestyle, or other risk factors between the groups contributed to the observed outcome differences. The lack of blinding and the potential for differential treatment during the follow-up period represent important sources of bias that reviewers of this literature have consistently acknowledged (PMC8614708, PMC7690390).

The ACCORD trial's finding of increased cardiovascular mortality with intensive therapy remains incompletely explained. The aggressive multi-drug regimen, the high rates of severe hypoglycemia, and the significant weight gain in the intensive group are all potential confounders that make it difficult to attribute the increased mortality specifically to the glycemic target rather than to the treatment approach. The ACCORD trial's results may not be generalizable to intensive therapy approaches that achieve similar HbA1c reductions with lower hypoglycemia risk — such as those using GLP-1 receptor agonists or SGLT2 inhibitors, which were not available at the time of the trial.

The observational studies examining glycemic variability and the legacy effect are subject to the inherent limitations of observational designs, including residual confounding, reverse causation, and selection bias. The Rio de Janeiro cohort study, while prospective and well-characterized, enrolled predominantly middle-aged to elderly patients with long-standing type 2 diabetes and high complication burden at a tertiary center — a population that may not represent patients with early or uncomplicated diabetes (PMC6389075). The study also did not correct for multiple comparisons, and with Bonferroni correction the predictive value for MACE and new microalbuminuria would be lost (PMC6389075).

The mechanistic evidence for epigenetic modifications as the substrate of metabolic memory, while compelling, is largely derived from in vitro cell culture experiments and animal models. The translation of these findings to human clinical contexts is not straightforward, and the specific epigenetic marks identified in experimental systems may not be the dominant mechanisms in human vascular disease. The epigenome profiling of DCCT patients provides the most direct human evidence, but this analysis was conducted in white blood cells rather than in vascular endothelial cells — the primary site of diabetic vascular damage — and the relationship between epigenetic marks in circulating cells and those in vascular tissues is not established.

The evidence base for the legacy effect is also limited by the relatively short follow-up periods of most trials. The ACCORD, ADVANCE, and VADT trials had median follow-ups of 3.5, 5, and 5.6 years, respectively — durations that may be insufficient to capture the full benefit of glycemic control, given that the UKPDS and DCCT/EDIC data suggest macrovascular benefits may only emerge after a decade or more (PMC10383300). The implication is that negative results from shorter trials should not be interpreted as evidence against the legacy effect, but rather as evidence that the follow-up period was insufficient to detect it.

The real-world evidence from the Korean emulated target trial comparing IIT with COAD (PMC12863771) is subject to the limitations inherent in retrospective observational designs, including residual confounding, misclassification bias, and confounding by indication (Korean guidelines recommend insulin for HbA1c ≥10%, meaning IIT patients may have had more severe baseline disease). The study population was restricted to Korean patients at tertiary hospitals, limiting generalizability to other ethnicities and healthcare systems. The propensity score matching did not fully balance fasting plasma glucose at baseline (SMD 0.338), representing residual imbalance.

The evidence for the legacy effect of dietary interventions is essentially absent in humans. The Oslo Cardiovascular Study suggested a 19% reduction in risk of death at first myocardial infarction (HR 0.71, 95% CI 0.51–1.00) at 40-year follow-up after a 5-year dietary intervention, but this finding is based on a single study with significant methodological limitations and potential confounding from concurrent lifestyle changes (PMC7690390). The near-absence of dietary intervention data in humans is attributable to difficulties in maintaining adherence, lack of specific dietary biomarkers, and funding constraints — and represents a major gap in the evidence base.

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### Comparative Effectiveness

#### Intensive Glycemic Control Versus Multifactorial Risk Factor Management

The comparison between intensive glycemic control alone and multifactorial risk factor management is one of the most important comparative effectiveness questions in diabetes care. The Steno-2 study's 21-year follow-up demonstrated that multifactorial intervention (simultaneously targeting glycemia, blood pressure, lipids, and microalbuminuria) produced a 45% reduction in all-cause mortality and a 62% reduction in cardiovascular mortality — effects that substantially exceed those achieved by glycemic control alone in any single-risk-factor trial (PMC7690390). The 50% reduction in cardiovascular and microvascular events during the active Steno-2 intervention period also exceeds the benefits seen in UKPDS or DCCT during their active periods (PMC10553000).

The ADVANCE post-trial follow-up showed a significant reduction in all-cause mortality (HR 0.91, 95% CI 0.84–0.99) and cardiovascular mortality (HR 0.88, 95% CI 0.77–0.99) in those patients originally treated with perindopril-indapamide compared to placebo, but intensive glucose control did not provide any long-term benefits during the post-trial follow-up (PMC7690390). This finding suggests that blood pressure control may be a more reliable generator of legacy effects in patients with established type 2 diabetes and cardiovascular risk factors.

The combined evaluation of arterial stiffness, glycemic control, and hypertension status in the Beijing Health Management Cohort (n=1,870 type 2 diabetes patients, median follow-up 4.0 years) demonstrated that patients with poor glycemic control and severe arterial stiffness had the highest risk of macrovascular complications (adjusted HR 2.73, 95% CI 1.42–5.25), and the highest cumulative composite risk score group had an adjusted HR of 3.36 (95% CI 1.56–7.25), with an AUC for the weighted composite score of 0.893 (PMC9706858).

#### Novel Pharmacological Agents and the Legacy Effect

The emergence of SGLT2 inhibitors and GLP-1 receptor agonists as cardiovascular outcome-modifying agents has added a new dimension to the legacy effect discussion. These agents reduce cardiovascular events through mechanisms that appear to be at least partially independent of their glucose-lowering effects — including hemodynamic effects, anti-inflammatory actions, and direct cardioprotective mechanisms (PMC6390346, PMC12467019). The cardiovascular outcome trials for these agents (EMPA-REG OUTCOME for empagliflozin, CANVAS for canagliflozin, DECLARE for dapagliflozin, LEADER for liraglutide) demonstrated significant reductions in cardiovascular events and, for SGLT2 inhibitors, in heart failure hospitalizations and renal outcomes (PMC6390346).

Whether these agents will generate a legacy effect comparable to that seen with early intensive glycemic control in DCCT/EDIC and UKPDS is unknown, as the cardiovascular outcome trials have not yet had sufficient post-trial follow-up to assess this question. However, the observation that SGLT2 inhibitor benefits on heart failure and renal outcomes appear largely independent of glycemic effects suggests that these agents may generate a legacy effect through mechanisms distinct from the epigenetic metabolic memory pathway — potentially through hemodynamic, anti-inflammatory, or direct organ-protective mechanisms (PMC6390346). A study from the AMD Annals database found that initiating SGLT2 inhibitor therapy soon after type 2 diabetes diagnosis significantly reduces long-term cardiovascular risk, suggesting that early use of these agents may generate a legacy effect analogous to that seen with early intensive glycemic control (PMC10910816).

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### Special Populations

#### Patients with Long-Standing Diabetes and Established Cardiovascular Disease

The evidence consistently indicates that the legacy effect is attenuated or absent in patients with long-standing diabetes and established cardiovascular disease. The ACCORD, ADVANCE, and VADT trials — all of which enrolled such patients — failed to demonstrate durable legacy benefits from intensive glycemic control, and ACCORD showed net harm (PMC8614708, PMC7690390). The VADT provided the most nuanced picture: a modest and transient cardiovascular legacy effect emerged at 10 years (HR 0.83, 95% CI 0.70–0.99) but disappeared at 15 years (HR 0.91, 95% CI 0.78–1.06), suggesting that even in patients with long-standing diabetes, some residual legacy benefit may exist but is not durable (PMC7690390). The clinical implication is that glycemic targets should be individualized based on disease duration and cardiovascular risk, with more lenient targets appropriate for patients with long-standing diabetes and established cardiovascular disease, where the risk of hypoglycemia may outweigh the potential legacy benefit.

#### Newly Diagnosed Type 2 Diabetes: The Critical Window

The evidence most strongly supports the legacy effect in patients with newly diagnosed type 2 diabetes who do not yet have established cardiovascular disease. The UKPDS enrolled patients within six months of diagnosis, and the Diabetes and Aging Study found that achieving near-normoglycemia in the first 12 months after diagnosis was necessary to generate a legacy effect (PMC7690390). The ADDITION study found that population-based diabetes screening — which enables earlier diagnosis and earlier intervention — was associated with a 21% lower risk of all-cause mortality and a 16% lower risk of cardiovascular events at 10-year follow-up (PMC7690390). These findings collectively support the concept of a "critical window" early in the disease course during which intensive glycemic control can establish a beneficial metabolic memory that persists for decades.

An emulated target trial using real-world electronic health record data from three major South Korean tertiary hospitals (n=2,092 newly diagnosed type 2 diabetes patients achieving HbA1c <7.0% after initial intensive therapy, 355 patients per group after 1:1 propensity score matching) found that initial intensive insulin therapy (IIT) was associated with a significantly lower risk of glycemic remission failure (adjusted HR 0.41, 95% CI 0.31–0.73) compared to combination oral antidiabetic drugs (COAD), with mean HbA1c remaining below 7.0% even at 3 years post-treatment in the IIT group (PMC12863771). The authors invoke the metabolic memory concept to explain these findings, suggesting that early insulin-based intensive therapy may establish a more durable glycemic legacy through β-cell preservation and recovery.

---

### Limitations of the Evidence Base

The evidence base for the legacy effect in diabetes is subject to several important methodological limitations that constrain the strength of conclusions that can be drawn.

The most fundamental limitation is that the definitive evidence for the legacy effect comes from only two landmark trials — DCCT/EDIC and UKPDS — and their post-trial follow-up phases, both of which were conducted in specific populations that may not be representative of the broader diabetes population. The generalizability of the legacy effect to patients with longer disease duration, established cardiovascular disease, or different ethnic backgrounds is directly contradicted by the ACCORD, ADVANCE, and VADT results.

The post-trial follow-up phases of DCCT/EDIC and UKPDS were observational rather than randomized, meaning that patients in both groups were free to receive any treatment after the trial ended, and unmeasured differences in treatment, lifestyle, or other risk factors between the groups may have contributed to the observed outcome differences (PMC8614708, PMC7690390).

The ACCORD trial's finding of increased cardiovascular mortality with intensive therapy remains incompletely explained, and the aggressive multi-drug regimen, high rates of severe hypoglycemia, and significant weight gain in the intensive group are all potential confounders that make it difficult to attribute the increased mortality specifically to the glycemic target.

The observational studies examining glycemic variability and the legacy effect are subject to residual confounding, reverse causation, and selection bias, and the Rio de Janeiro cohort study enrolled a population that may not represent patients with early or uncomplicated diabetes (PMC6389075).

The mechanistic evidence for epigenetic modifications as the substrate of metabolic memory is largely derived from in vitro cell culture experiments and animal models, and the translation of these findings to human clinical contexts is not straightforward.

The evidence base is also limited by the relatively short follow-up periods of most trials, with ACCORD, ADVANCE, and VADT having median follow-ups of 3.5, 5, and 5.6 years — durations that may be insufficient to capture the full benefit of glycemic control given that macrovascular benefits may only emerge after a decade or more (PMC10383300).

Attrition during post-trial follow-up can reach 25–30% of subjects included in the trial, compromising data completeness and potentially introducing selection bias in the post-trial analyses (PMC7690390).

Publication bias — the tendency to publish positive results more readily than negative ones — may have contributed to an overestimate of the legacy effect in the literature, as trials that failed to show legacy benefits may have received less attention than those that did (PMC7690390).

The evidence for the legacy effect of dietary interventions is essentially absent in humans, representing a major gap in the evidence base that limits the ability to make recommendations about non-pharmacological approaches to establishing a beneficial metabolic memory (PMC7690390).

Most landmark trials were conducted in predominantly Western, older populations, and the applicability of the legacy effect concept to younger, more diverse, or lower-income populations is uncertain. The increasing prevalence of type 2 diabetes in younger people — who experience more rapid disease progression and greater life-years lost — represents a particularly important gap in the evidence base (PMC6390346).

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### Conclusions and Future Directions

#### What the Evidence Supports

The evidence from DCCT/EDIC and UKPDS, supported by the Steno-2 study and multiple observational cohorts, firmly establishes that early intensive glycemic control in patients with newly diagnosed or early-stage diabetes — both type 1 and type 2 — confers durable benefits on microvascular and macrovascular outcomes that persist for years to decades beyond the active intervention period, even after HbA1c levels between groups have converged. In type 1 diabetes, the DCCT/EDIC demonstrated a 57% reduction in cardiovascular events (HR 0.43, 95% CI 0.12–0.79) and a 46% reduction in nephropathy (HR 0.54, 95% CI 0.34–0.84) during 17 years of post-trial follow-up, despite convergence of HbA1c within one year of the trial's end (PMC8614708, PMC7690390). In type 2 diabetes, the UKPDS post-trial follow-up demonstrated persistent risk reductions for myocardial infarction (RR 0.85, 95% CI 0.74–0.97) and all-cause mortality (RR 0.87, 95% CI 0.79–0.96) a decade after HbA1c differences had disappeared (PMC7690390). The Steno-2 study demonstrated that multifactorial intensive intervention in type 2 diabetes with microalbuminuria delayed death and first cardiovascular event by approximately 8 years at 21-year follow-up (PMC7690390).

The evidence supports the conclusion that the legacy effect is most robust when: (1) intervention is initiated early in the disease course, before cardiovascular disease is established; (2) the patient does not have long-standing poorly controlled diabetes with pre-existing epigenetic damage; (3) the intervention is comprehensive, targeting multiple cardiovascular risk factors simultaneously; and (4) the glycemic reduction is achieved gradually rather than rapidly, to avoid the adverse effects of treatment-induced neuropathy, early retinopathy worsening, and hypoglycemia-related cardiovascular risk (PMC8614708, PMC7690390, PMC10383300).

The mechanistic evidence strongly supports epigenetic reprogramming — particularly histone methylation (H3K4me1 by Set7/9 at the RELA promoter), histone acetylation, and CpG methylation changes — as the molecular substrate of metabolic memory, with AGE accumulation, ROS generation, and NF-κB activation as the upstream drivers and downstream effectors of this epigenetic damage (PMC8614708, PMC7690390). Glycemic variability contributes independently to this epigenetic damage, suggesting that the pattern of glucose exposure — not just its mean level — shapes the metabolic legacy (PMC7792304, PMC6389075).

#### What the Evidence Does NOT Support

The evidence does not support the conclusion that intensive glycemic control confers a legacy benefit in all patients with type 2 diabetes, regardless of disease duration or cardiovascular risk profile. The ACCORD, ADVANCE, and VADT trials clearly demonstrate that intensive glycemic control in patients with long-standing type 2 diabetes and established or high cardiovascular risk does not produce durable legacy benefits and may cause net harm through hypoglycemia and weight gain (PMC8614708, PMC7690390, PMC10383300). The evidence does not support targeting HbA1c <6.0% in such patients, as the ACCORD trial demonstrated a 35% increase in cardiovascular mortality with this approach (PMC10383300).

The evidence does not support the conclusion that the legacy effect is equivalent for all cardiovascular risk factors. The UKPDS blood pressure arm's failure to show a durable legacy effect, in contrast to the glycemic arm's robust legacy, suggests that the epigenetic mechanisms underlying metabolic memory may be specific to hyperglycemia-induced damage and may not apply equally to blood pressure-related vascular injury (PMC7690390). The evidence does not support the conclusion that dietary interventions alone can generate a legacy effect in humans, as no well-designed human trial has demonstrated this (PMC7690390).

The evidence does not support the conclusion that HbA1c alone is a sufficient metric for assessing the risk of metabolic memory and its vascular consequences. The Rio de Janeiro cohort study found that glycemic variability was a better predictor than mean HbA1c for most micro- and macrovascular outcomes in fully adjusted models (PMC6389075), and mechanistic evidence demonstrates that glycemic variability can imprint epigenetic damage independently of mean glucose levels (PMC7792304).

#### Future Research Directions

**1. Epigenetic biomarkers for legacy effect risk stratification.** The identification of specific epigenetic signatures — histone methylation marks, CpG methylation patterns, miRNA profiles — that predict the presence or absence of a beneficial or adverse metabolic memory would enable personalized glycemic targets and treatment strategies. The epigenome profiling of DCCT patients provides a proof-of-concept for this approach, but larger, prospective studies with standardized epigenomic assays are needed (PMC8614708).

**2. Optimal timing and duration of intensive therapy for legacy effect induction.** The critical window for establishing a beneficial metabolic memory is not precisely defined. Prospective studies that randomize patients to intensive therapy at different time points after diagnosis — and follow them for decades — are needed to define the optimal timing and duration of intensive therapy for legacy effect induction. The Diabetes and Aging Study's finding that HbA1c ≥6.5% in the first year after diagnosis was associated with higher long-term risk provides a starting point, but more granular data are needed (PMC7690390).

**3. Legacy effects of novel pharmacological agents.** The cardiovascular outcome trials for SGLT2 inhibitors and GLP-1 receptor agonists have demonstrated significant cardiovascular and renal benefits, but post-trial follow-up data to assess legacy effects are not yet available. Long-term follow-up studies of these trials — analogous to EDIC for DCCT — are urgently needed to determine whether these agents generate durable legacy benefits and through what mechanisms (PMC6390346, PMC12467019).

**4. Glycemic variability as a therapeutic target for legacy effect optimization.** If glycemic variability contributes independently to epigenetic damage and metabolic memory, then reducing variability — through continuous glucose monitoring, time-in-range optimization, and pharmacological strategies that minimize glucose fluctuations — may be as important as reducing mean HbA1c for establishing a beneficial legacy. Randomized trials that specifically target glycemic variability reduction and assess long-term vascular outcomes are needed to test this hypothesis (PMC7792304, PMC6389075).

**5. Reversibility of adverse metabolic memory.** The question of whether the adverse metabolic memory established by prolonged poor glycemic control can be reversed — and if so, by what interventions — is of enormous clinical importance. Epigenetic therapies including HDAC inhibitors, histone methyltransferase inhibitors, and siRNAs targeting epigenetic modifiers have shown promising results in experimental diabetes models, but clinical translation has not yet been demonstrated (PMC8614708). Trials of epigenetic-modifying agents in patients with established adverse metabolic memory represent a high-priority research direction.

**6. Legacy effects in younger and more diverse populations.** The increasing prevalence of type 2 diabetes in younger people — who experience more rapid disease progression and greater life-years lost — makes the legacy effect concept particularly relevant for this population, yet the evidence base is almost entirely derived from older adults. Studies specifically designed to assess the legacy effect in younger patients with type 2 diabetes, and in diverse ethnic populations, are urgently needed (PMC6390346).

**7. Multifactorial intervention and the synergistic legacy effect.** The Steno-2 study's dramatic 21-year legacy effect from multifactorial intervention has not been reproduced in subsequent studies. Understanding the specific components of the Steno-2 intervention that drove the legacy effect — and whether similar results can be achieved in larger, more diverse populations — is a critical research priority. The design of a large, multicenter trial of early multifactorial intensive intervention in newly diagnosed type 2 diabetes with long-term follow-up would be the definitive test of the multifactorial legacy effect hypothesis (PMC7690390).

**8. Dietary interventions and the legacy effect.** The near-complete absence of human evidence for a dietary legacy effect represents a major gap in the evidence base. Well-designed, long-term dietary intervention trials with post-intervention follow-up — analogous to the pharmacological legacy effect trials — are needed to determine whether dietary patterns can establish a beneficial metabolic memory. The Oslo Cardiovascular Study's 40-year follow-up provides a proof-of-concept, but more rigorous designs with better dietary adherence monitoring and longer follow-up are needed (PMC7690390).

In summary, the legacy effect represents one of the most important and clinically actionable concepts in diabetes medicine. The evidence firmly establishes that early intensive glycemic control in newly diagnosed diabetes — both type 1 and type 2 — can establish a beneficial metabolic memory that protects against microvascular and macrovascular complications for decades. The molecular substrate of this memory lies in epigenetic reprogramming driven by hyperglycemia-induced oxidative stress, AGE accumulation, and inflammatory signaling. The clinical imperative is clear: early diagnosis, early intensive intervention, and comprehensive risk factor management represent the most powerful tools available for preventing the long-term vascular consequences of diabetes. The challenge for the next generation of research is to define the precise conditions under which the legacy effect can be reliably induced, to identify biomarkers that predict its presence or absence, and to develop interventions that can reverse the adverse metabolic memory established by prolonged poor glycemic control.

## References

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