Highlights
Achievement of prediabetes remission—restoring normal glucose regulation—is associated with a 50% to 60% reduction in the long-term risk of cardiovascular death and hospitalization for heart failure.
Data from two major international cohorts (DPPOS in the US and DaQingDPOS in China) confirm a durable ‘legacy effect’ that persists for 20 to 30 years after the initial intervention.
The protective benefit of remission remains robust across diverse ethnic populations and regardless of the specific lifestyle or pharmacological interventions used to achieve glycemic normalization.
The Prediabetes Paradigm Shift: From Delay to Remission
For decades, the clinical management of prediabetes has focused primarily on delaying the onset of overt type 2 diabetes. However, mounting evidence suggests that the microvascular and macrovascular damage associated with dysglycemia begins long before the traditional diagnostic threshold for diabetes is met. Prediabetes is not merely a precursor state; it is a significant risk factor for cardiovascular disease (CVD) and heart failure (HF).
While multicomponent lifestyle interventions focusing on weight loss and physical activity are the gold standard for prediabetes management, their long-term impact on hard cardiovascular endpoints has remained a subject of debate. The concept of ‘remission’—the restoration of normal glucose regulation (NGR)—has recently emerged as a potentially superior clinical target. This new analysis, published in Lancet Diabetes & Endocrinology, provides the strongest evidence to date that reaching remission offers a decades-long shield against the most severe cardiovascular complications.
Study Design: Bridging Two Continents and Three Decades
The research comprises post-hoc analyses from two of the most influential diabetes prevention trials in medical history: the US-based Diabetes Prevention Program Outcomes Study (DPPOS) and the Chinese DaQing Diabetes Prevention Outcomes Study (DaQingDPOS).
The US DPPOS Cohort
The DPPOS included 2,402 participants who were followed from the start of the original trial in 1996 through early 2020. Remission was assessed using American Diabetes Association (ADA) criteria after one year of intervention. The researchers employed inverse probability of treatment weighting to adjust for baseline differences between those who achieved remission and those who did not, ensuring a rigorous comparison over a median follow-up of 20 years.
The DaQingDPOS Cohort
The DaQing study provided a unique long-term perspective from a Chinese population. It included 540 participants, with remission assessed after six years of intervention. The follow-up period for this cohort extended to 30 years, providing a rare window into the lifelong trajectory of cardiovascular risk following early glycemic intervention.
Endpoints and Meta-analysis
The primary endpoint for both studies was a composite of cardiovascular death or hospitalization for heart failure. To strengthen the findings, the researchers conducted a unifying meta-analysis across both datasets to determine the overall effect on the primary endpoint and all-cause mortality.
Key Findings: A Legacy of Remission
The results from both cohorts were remarkably consistent, pointing toward a significant ‘legacy effect’ of early glycemic normalization.
DPPOS Results
In the US cohort, 11.5% of participants reached remission after one year. Over the 20-year follow-up, the event rate for the primary composite endpoint was 1.74 per 1,000 person-years in the remission group, compared to 4.17 per 1,000 person-years in the non-remission group. This translated to a fully adjusted hazard ratio (HR) of 0.41 (95% CI 0.20–0.84; p=0.014). Essentially, those who achieved remission at the one-year mark reduced their risk of CV death or HF hospitalization by 59%.
DaQingDPOS Results
The Chinese cohort mirrored these findings. The hazard ratio for the primary endpoint in the DaQing study was 0.49 (95% CI 0.28–0.84; p=0.010), demonstrating a 51% risk reduction. The stability of these results across 30 years of follow-up underscores the profound durability of the benefit associated with returning to normal glucose levels.
Pooled Meta-analysis
When the data were pooled, the results remained highly significant. Furthermore, the researchers analyzed the composite endpoint for participants who reached remission at least once during the follow-up period. This broader definition of remission still yielded a powerful protective effect, with a hazard ratio of 0.43 (95% CI 0.29–0.63; p<0.0001).
Clinical Significance and Mechanistic Insights
The discovery that a brief period of normal glucose regulation can alter the cardiovascular trajectory for 20 to 30 years has major implications for clinical practice. This ‘legacy effect’ suggests that the early reversal of metabolic dysfunction prevents irreversible damage to the myocardium and the vascular endothelium.
Potential mechanisms for this protection include:
1. Reduced Glucotoxicity: Normalizing glucose levels limits the formation of advanced glycation end-products (AGEs), which are known to cause structural stiffening of the heart and blood vessels.
2. Improved Endothelial Function: Early intervention may preserve the glycocalyx and endothelial nitric oxide production, maintaining vascular health before atherosclerotic changes become permanent.
3. Metabolic Memory: The study supports the theory of ‘metabolic memory,’ where early glycemic control ‘programs’ the cells to resist inflammatory and oxidative stress pathways that typically lead to heart failure and cardiovascular death.
Expert Commentary and Limitations
Clinicians should view these findings as a call to action to move beyond passive monitoring of prediabetes. While ‘watchful waiting’ has often been the default, these data suggest that an aggressive push toward remission—using intensive lifestyle modification and, where appropriate, pharmacotherapy—could be one of the most effective primary prevention strategies for heart failure and cardiovascular mortality available today.
However, some limitations must be considered. As a post-hoc analysis, the study cannot definitively prove a causal relationship between remission and outcome, though the use of inverse probability weighting in the DPPOS helps mitigate selection bias. Additionally, the criteria for remission were based on specific time points (1 year for DPPOS and 6 years for DaQing), and the impact of fluctuating glucose levels over time requires further investigation.
Conclusion: A New Approach to Cardiovascular Prevention
The post-hoc analyses of the DPPOS and DaQingDPOS trials provide compelling evidence that prediabetes remission is not just a metabolic milestone, but a critical cardiovascular safeguard. By halving the risk of cardiovascular death and heart failure over a 30-year horizon, reaching normal glucose regulation represents a high-value target for both individual clinicians and public health policymakers. Shifting the focus from ‘preventing diabetes’ to ‘achieving remission’ may be the key to reducing the global burden of cardiovascular disease.
Funding and Trial Information
The study was funded by several institutions, including the German Center for Diabetes Research (DZD), the German Federal Ministry of Research, Technology and Space, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for the DPPOS. The DaQing study received support from the Centers for Disease Control and Prevention (CDC), the WHO, and various Chinese medical institutions. ClinicalTrials.gov identifiers include NCT00004992 (DPP) and NCT00038727 (DPPOS).
References
1. Vazquez Arreola E, Gong Q, Hanson RL, et al. Prediabetes remission and cardiovascular morbidity and mortality: post-hoc analyses from the Diabetes Prevention Program Outcome study and the DaQing Diabetes Prevention Outcome study. Lancet Diabetes Endocrinol. 2025 Dec 12:S2213-8587(25)00295-5.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
3. Gong Q, Zhang P, Wang J, et al. Changes in life expectancy and effects of lifestyle intervention in type 2 diabetes: 30-year follow-up of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol. 2019;7(6):452-461.
