Non-diabetes status after diagnosis of impaired glucose tolerance and risk of long-term death and vascular complications: A post hoc analysis of the Da Qing Diabetes Prevention Outcome Study

Type 2 diabetes is associated with an increased risk of death, disability, and fatal vascular complications and poses a significant economic burden on individuals and societies worldwide [1], especially in China [2]. Researchers have made extensive efforts to prevent diabetes and obtained strong evidence and important achievements that have changed our knowledge of whether diabetes can be prevented. Among individuals with impaired glucose tolerance (IGT), lifestyle interventions (diet and/or exercise) are feasible and effective in delaying and decreasing the incidence of diabetes [3] and are more effective than metformin in high-risk populations [4].

The 3 “landmark” diabetes prevention studies reported long-term follow-up outcomes in individuals with IGT after lifestyle or metformin intervention. The Diabetes Prevention Program Outcomes Study (DPPOS) found that during a 21-year follow-up period, regression to normal glucose tolerance (NGT) was associated with a lower prevalence of microvascular diseases [5], whereas neither metformin nor lifestyle intervention reduced cardiovascular events [6]. The Finnish Diabetes Prevention Study (DPS) found no reduction in cardiovascular morbidity in individuals with IGT during the first 10-year follow-up [7]. The Da Qing Diabetes Prevention Study (DQDPS) and Outcomes Study (DQDPOS) found that lifestyle modifications were associated with all-cause and cardiovascular disease (CVD)-related deaths [8]. A recent study reported that the incidence of all-cause death, cardiovascular death, CVD events, and composite microvascular complications in a lifestyle intervention group was significantly lower than that in controls [9].

The American Diabetes Association released the “Prevention or Delay of Type 2 Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2023” [10], which reported that lifestyle intervention in individuals with a high risk of type 2 diabetes affected the risk of CVD [11] and reduced the risk of long-term microvascular in the DPPOS and DQDPS [12,13]. The effect of lifestyle interventions on the prevention of CVD and death has also been demonstrated in the DQDPOS [8,9]. However, these clinical practice recommendations do not specify the target number of years for delaying the onset of diabetes through lifestyle interventions to prevent the associated comorbidities.

At the end of 1988, 539 participants remained alive, with 70 having diabetes and 469 remaining non-diabetes. At the end of 1990, 176 of the 533 participants had been diagnosed with diabetes and 357 had not. At the end of 1992, 520 patients were alive, including 254 who progressed to diabetes and 266 who did not (Table 1).

Table 2 shows the influence of the years of maintaining a non-diabetes status after diagnosis of IGT on death and vascular complications in all participants. At the end of the key point of 2 years, there was no significant difference in death and vascular complication rates per 1,000 person-years between those who remained non-diabetes for 2 years and those who progressed to diabetes during the same period (p > 0.05). HRs (non-diabetes versus diabetes) for all-cause and CVD death were 0.82 (95% CI: 0.59 to 1.15, p = 0.25) and 0.998 (95% CI: 0.60 to 1.66, p = 0.99), respectively, and macro- and microvascular complications were 0.91 (95% CI: 0.65 to 1.27, p = 0.57) and 0.77 (95% CI: 0.50 to 1.18, p = 0.23), respectively (Fig 1A).

At the end of key point of 4 years, the rates of vascular complications in individuals remaining non-diabetes status were lower than in those who progressed to diabetes. The rates per 1,000 person-year were 26.2 (22.6 to 30.3) versus 40.7 (34.1 to 48.6) for cardiovascular events and 14.9 (12.4 to 17.9) versus 21.9 (17.5 to 27.5) for microvascular disease (all p p = 0.026). The risk of vascular complications decreased by 40% in these individuals (HR: 0.63; 95% CI: 0.49 to 0.82; p p = 0.004 for macro- and microvascular complications, respectively [Fig 1B]).

At the end of the key point of 6 years, the rates per 1,000 person-years for death and vascular complications were significantly different between individuals remaining non-diabetes status for 6 years and those who progressed to diabetes (all p p = 0.002) (Fig 1C). At the end of 6 years, the risk of each outcome was 40% lower in the non-diabetes group than in the diabetes group, even after adjusting for medications (all p Table 2).

Fig 2 shows the log-rank p-values of the cumulative incidence of CVD events and death between the non-diabetes and diabetes groups at the end of 4 years (Fig 2A and 2B) and at the end of 6 years (Fig 2C and 2D) at different follow-up years. At the end of 4 years, the log-rank p-values for CVD events were 0.13 and 0.005 at 20 and 25 years of follow-up, respectively (Fig 2A). At the end of 6 years, the log-rank p-value for CVD events was 0.0467 over 15 years of follow-up (Fig 2C). For cardiovascular death, the log-rank p-value was less than 0.05 only at the end of 6 years over the 28-year follow-up period (Fig 2B and 2D).

Fig 2. Kaplan–Meier failure curves of cardiovascular death and events at the end of key point of 4 and 6 years.

(A) CVD events at the end of 4 years, (B) CVD death at the end of 4 years, (C) CVD events at the end of 6 years, and (D) CVD death at the end of 6 years. CVD, cardiovascular disease. At the end of 2 years: during the period from 1986 to 1988; at the end of 4 years: during the period from 1986 to 1990; at the end of 6 years: during the period from 1986 to 1992; non-diabetes included individuals remaining IGT or regression to normal glucose tolerance; diabetes included individuals who progressed to diabetes.

https://doi.org/10.1371/journal.pmed.1004419.g002

Table 3 shows the influence of the years of maintaining a non-diabetes status after diagnosis of IGT on death and vascular complications in the original intervention group. The results were consistent with those in the whole study population. At the end of 2 years, the risk of each outcome reduced; however, the changes were not statistically significant (p > 0.05). At the end of 4 years, the risk of all-cause death (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.026) and vascular complications (HR; 0.59; 95% CI: 0.43 to 0.80; p = 0.001 and HR: 0.61; 95% CI: 0.42 to 0.90; p = 0.012 for macro- and microvascular disease, respectively) was lower in individuals who remained non-diabetes status than in those who progressed to diabetes. These differences persisted at the end of 6 years. At the end of 6 years, the risk of cardiovascular death reduced by 50% (HR: 0.52; 95% CI: 0.33 to 0.80; p = 0.003). The baseline clinical characteristics are shown in S1 Table.

Although extremely important, the years of maintaining a non-diabetes status after diagnosis of IGT is only one of the most important factors influencing the risk of long-term outcomes. The mechanisms underlying the different long-term outcomes are complex. The DPPOS discussed the influence of post-trial overuse of medication for the treatment of hypertension, hyperglycaemia, and dyslipidaemia on outcomes, which may mask the beneficial influence of lifestyle interventions on these outcomes [16]. The present post hoc analysis revealed that the reduction in the risk of vascular complications remained significant after adjusting for medications. Additionally, compared with participants in the DPPOS and DPS, those in the DQDPS were younger (45.2 ± 9.3 [DQDPS] versus 50.5 ± 11 [DPPOS] and 55 ± 7 [DPS] years), had a lower percentage of female (45.8% [DQDPS] versus 68.5% [DPPOS] and 67.1% [DPS]), and had a lower BMI (25.7 ± 7.6 [DQDPS] versus 34 ± 6.7 [DPPOS] and 31.5 ± 4.5 [DPS] kg/m²) [17]. These differences in the ethnicity of the studied populations and the intensity of the intervention may have contributed to the outcomes. Nevertheless, the difference in the duration of lifestyle interventions among the 3 diabetes prevention studies remains one of the most important differences [3,4,18]. Therefore, one possible explanation is that the different durations of the interventions across the three studies may have affected the years of maintaining a non-diabetes status, which is associated with the long-term risk of death and vascular complications. An intervention that lasts for several years is needed to observe its apparent effects on death and vascular complications; however, it is difficult to establish a control group and implement long-term follow-up.

We recently reported that about 90% of the participants in DQDPS progressed to diabetes during the 20 years follow-up period. Furthermore, the China Diabetes Prevention Program (CDPP) reports that currently Chinese with prediabetes face a high risk of developing diabetes and the initial combination of metformin and lifestyle intervention modification (LSM) showed a better effect of preventing diabetes than LSM alone [19]. Therefore, it may be logical to assume that the combined use of metformin and LSM may be more effective in prolonging diabetes free time.

The question arises as to why remaining several years of non-diabetes status after diagnosis of IGT can affect clinical outcomes over decades of follow-up. Studies on diabetes have demonstrated that strict, early, glycaemic control can improve long-term adverse outcomes through a phenomenon called the “legacy” effect. The 10-year post-trial follow-up of the United Kingdom Prospective Diabetes Study showed that the risk of myocardial infarction and all-cause death was continuously lower in both intensive management groups compared with the standard management group in participants with newly diagnosed type 2 diabetes [20]. This demonstrates that early improvements in glycaemic control have a legacy effect, which reduces the risk of coronary events and death from any cause. A similar legacy effect has been demonstrated in 3 studies on diabetes prevention. These studies showed that the effect of a 3- to 6-year lifestyle intervention on diabetes prevention extended to a post-trial follow-up period of more than 10 years [21–23]. Our previous study reported that the median delay in diabetes duration in individuals who remained non-diabetes status for 6 years was 17 years [15]. Hence, it is easy to understand why time-limiting lifestyle interventions decrease the subsequent long-term risk of adverse clinical outcomes.

Follow-up time is another important factor in determining the positive association between vascular complications and death and maintaining non-diabetes time. Compared with the DPPOS (21-year follow-up) and DPS (13-year follow-up), the DQDPS had a follow-up time of more than 30 years. In the DQDPS, a significant reduction in the long-term risk of vascular complications and death did not occur in the same follow-up period as DPPOS, but gradually. The incidence in microvascular complications [13], death (cardiovascular and all-cause) [8], and all micro- and macrovascular complications and death [9] was significantly reduced in the 20-, 23-, and 30-year follow-up studies, respectively. Furthermore, in a 30-year follow-up study, individuals who still had IGT at the end of a 6-year trial had significantly lower incidences of death and vascular complications than those who developed diabetes [15]. This shows that a short follow-up period may not elucidate the “real” result of vascular outcomes, which needs a decades-long post-trial follow-up. Our post hoc analysis explored the combined influence of maintaining non-diabetes time (4 to 6 years) and post-trial follow-up (>30 years) on death and macrovascular complications. To prevent diabetes among the Chinese IGT population, maintaining a non-diabetes status for a minimum of 4 years combined with 25 years of post-trial follow-up may be needed to reduce the risk of macrovascular complications and death significantly. Concerning Western populations, which usually have a higher BMI than Asian populations, the number of years of maintaining a non-diabetes status after diagnosis of IGT are required to reduce the risk of these clinical outcomes remains under investigation.

This post hoc analysis has several strengths. First, the data used in this study are from the world’s first randomized lifestyle intervention study on the prevention of diabetes, and a previous report proved that lifestyle intervention in individuals with IGT could effectively delay the onset of diabetes during the trial and for more than 10 years after trial completion. Second, the cohort was followed up for more than 30 years and revealed that time-limited lifestyle interventions could reduce the long-term cumulative incidence of all-cause death, cardiovascular death, and vascular complications [24]. Third, the study had the longest intervention time and longest duration of post-trial follow-up among other similar diabetes intervention trials worldwide.