Prediabetes remission can have long-term benefits

Prediabetes is a metabolic condition characterized by blood sugar levels that are higher than normal but have not yet reached the clinical threshold for a Type 2 diabetes diagnosis, commonly defined by an A1C of 5.7–6.4% (or fasting glucose 100–125 mg/dL). It currently affects an estimated 38 percent of U.S. adults. Risk factors are the same as those for Type 2 diabetes including excess weight, poor diet, insufficient exercise, age, smoking, and family history.

While prediabetes serves as a significant warning sign, progression to full-blown diabetes is not inevitable. Through intensive lifestyle interventions such as diet and exercise, or the use of medications like metformin, and now more recently GLP-1 agonists, individuals can delay the onset of the disease or even achieve "remission" by returning their glucose to a normal range. However, if left unmanaged, both prediabetes and diabetes carry severe health risks, ranging from increased systemic inflammation to reduced insulin sensitivity. Most notably, these conditions are major drivers of cardiovascular disease, significantly increasing the long-term risk of heart attacks, hospitalizations for heart failure, and premature death.

A recent study published in Lancet Diabetes & Endocrinology performed an observational post-hoc analysis (planned after data seen) using two long-running diabetes-prevention trial cohorts: DPPOS (the long-term follow-up of the US Diabetes Prevention Program) and DaQingDPOS (a similar trial in China). In the original U.S. trial, intensive lifestyle programs (diet and exercise) reduced the development of Type 2 diabetes by 58%, while the drug metformin reduced it by 31%.  However quite surprisingly, there was not statistically significant reductions in major adverse cardiovascular events (MACE) or mortality after 21 years of follow-up. On the other hand, the original DaQing study found that 6 years of lifestyle intervention led to a 33% reduction in cardiovascular mortality and a 26% reduction in all-cause mortality over 30 years.

In the recent post-hoc follow-up, the key comparison was between participants who achieved prediabetes "remission" versus those who did not, rather than treatment (i.e. lifestyle intervention) versus control. According to American Diabetes Association (ADA) criteria, the study defined remission as the simultaneous achievement of a fasting plasma glucose level under 100 mg/dL, a 2-hour plasma glucose under 140 mg/dL, and an A1C below 5.7%. Remission was assessed at the one-year mark for the U.S. cohort and at the end of the six-year intervention period for the Chinese cohort. Median follow-up durations were 20 and 30 years, respectively. There were 2402 participants DPPOS and 540 in DaQingDPOS. 

The primary endpoint in both cohorts was a composite of cardiovascular death or hospitalization for heart failure. DPPOS also evaluated secondary outcomes including MACE, cardiovascular death, HF hospitalization, and all-cause mortality.  

The results of the post-hoc analysis across both trials demonstrated that achieving prediabetes remission led to a substantial long-term reduction in cardiovascular events and mortality. In the U.S.-based DPPOS cohort, 11.5% of participants reached remission at the one-year mark. This group experienced a 59% reduction in the risk of cardiovascular death or heart failure hospitalization (adjusted HR=0.41, Figure 1) and was significantly less likely to develop Type 2 diabetes (34% vs. 57%) compared to those who did not reach remission. These findings were validated by the Chinese DaQingDPOS study (13.3% attained remission), which reported a 51% lower risk for the primary cardiovascular endpoint (adjusted HR=0.49) and a 45% lower risk of all-cause mortality (adjusted HR=0.55) over 30 years. A pooled meta-analysis of the two studies showed a consistent 53% reduction in the risk of cardiovascular death or heart failure hospitalization (p <.001) and a 37% reduction in all-cause mortality (p = .0014). 

One key question is whether the salutary effects were due to avoiding or postponing the onset of type 2 diabetes or the more direct result of prediabetes remission (i.e. the remission could be temporary but the benefit was sustained). The paper’s takeaway is that the lower cardiovascular/heart-failure risk in the remission group was not explained mainly (or entirely) by simply avoiding type 2 diabetes. The researchers used a specific model that adjusted for time-dependent diabetes (accounting for if and when a person developed the disease during the 20- to 30-year follow-up). Even after this adjustment, the reduction in risk for heart failure and cardiovascular death remained robust and statistically significant. More specifically, the HR adjusted for time-dependent diabetes was 0.5 compared to 0.47 (not adjusted for diabetes) for the primary endpoint of cardiovascular death or heart failure hospitalization. Thus, based on this statistical analysis avoiding or postponing the onset of type 2 diabetes had a very modest impact on health compared to the remission itself.

Thus, the authors conclude that returning to a normal glucose level, even for a relatively short period, creates a "legacy effect." This physiological shift provides long-term protection to the heart that lasts for decades, regardless of the patient's future glucose trajectory. This is an intriguing conclusion that needs to be further tested (i.e. larger trials); one concern is that type 2 diabetes onset may still be a confounding factor despite the statistical adjustments made in the paper.

Crucially, the researchers emphasize that the benefits of remission extend beyond simple weight loss; reaching normal glucose levels appears to encapsulate broader metabolic improvements, such as enhanced insulin sensitivity, reduced visceral fat, and lower systemic inflammation, which are all possible physiologic mechanisms of the legacy effect. In this day and age of GLP-1 agonists helping people to lose significant amounts of weight, the paper argues that blood glucose control is also important, and of course the two often go together.

Figure 1. Kaplan–Meier risk curves for primary outcome of cardiovascular death or hospitalization

for heart failure in U.S. Diabetes Prevention Program Outcomes Study (DPPOS). Remission status was determined after 1 year of lifestyle intervention, with subjects followed for a median additional 20 years. Non-remission subjects (blue line) showed higher cumulative incidence than remission subjects (green line) with an adjusted HR = 0.41, p = 0.014 (Arreola et al. Lancet Diabetes & Endocrinology, 2026).