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In a multi‐ethnic population‐based cohort study adjusted for cardiovascular risk factors, it was shown that subjects with IFG have a higher prevalence of unrecognized MIs than those with NFG, with an odds ratio of 1.60 (95% CI 1.01–2.48).

      In the Whitehall Study, after 5–10 years of follow‐up, survival by baseline glucose tolerance status diverged among the groups, and median survival differed by approximately 4 years between the normoglycemic and glucose intolerant groups [70]. Overall, all‐cause mortality, cardiovascular mortality, and respiratory mortality were higher among participants with glucose intolerance. The hazard of coronary mortality rose beginning at a 2‐h PG of 83 mg/dL; however, the graded relationship diminished after adjusting for multiple variables including baseline CVD.

      A systematic review and meta‐analysis incorporated 53 prospective studies with 1 611 339 subjects who were followed for a median of 9.5 years for cardiovascular and mortality outcomes [68]. IFG and IGT diagnostic criteria were in accordance with 2020 ADA guidelines [1]. Compared to individuals with normoglycemia, those with IGT or IFG had an increased risk of composite CVD (relative risk (RR) 1.13 for IFG and 1.30 for IGT), coronary heart disease (RR 1.10 for IFG and 1.20 for IGT), stroke (RR 1.06 for IFG and 1.20 for IGT), and all‐cause mortality (RR 1.13 for IFG and 1.32 for IGT). One limitation of this systematic review and meta‐analysis is that some of the included studies did not adjust for progression to DM during the follow‐up period.

A separate meta‐analysis examined 102 prospective studies with 698 782 subjects and showed that FPG was modestly and non‐linearly associated with vascular disease, with hazard ratios for coronary heart disease of 1.11 for FPG of 5.6–6.09 mmol/L and 1.17 for FPG of 6.1–6.99 mmol/L [71]. Another meta‐analysis that included 97 prospective studies with 820 900 subjects calculated hazard ratios for cause‐specific death according to baseline FPG [72]. After adjusting for multiple variables and excluding subjects with known CVD at baseline, FPG was found to be nonlinearly related to risk of death. Compared with subjects with NFG, subjects with IFG had hazard ratios of 1.13 for cancer deaths, 1.17 for vascular deaths, and 1.12 for non‐cancer and non‐vascular deaths.

Management of prediabetes

      The goals of prediabetes management include preserving β‐cell function, delaying or preventing the onset of DM, delaying or preventing the developing of microvascular and macrovascular complications associated with hyperglycemia, and reducing the cost of diabetes care.

      Diabetes prevention program

      The Diabetes Prevention Program (DPP) enrolled 3234 nondiabetic adult subjects at 27 centers in the U.S. [18]. Eligibility criteria included FPG of 95–125 mg/dL and a 2‐h PG during a 75‐g OGTT 140–199 mg/dL. Subjects were assigned to one of three groups: (1) intensive lifestyle modification (goal ≥ 7% weight loss of initial body weight and ≥ 150 minutes of moderate intensity physical activity/week); (2) metformin 850 mg twice daily plus standard lifestyle recommendations; or (3) placebo plus standard lifestyle recommendations. Standard lifestyle recommendations were provided in writing and through annual brief individual sessions [73]. In contrast, the intensive lifestyle modification provided comprehensive instruction in a structured 16‐lesson curriculum.

      The original DPP results were published after an average follow‐up of 2.8 years. The estimated cumulative incidence of DM at three years was significantly different among all groups: 28.9% in the placebo group; 21.7% in the metformin group; and 14.4% in the intensive lifestyle group. Weight loss was the main predictor of reduced DM incidence, with a hazard ratio per five‐kilogram (kg) weight loss of 0.42 (95% CI 0.35–0.51). Further, for every one kg of weight loss, there was a 16% reduction in risk of progression to DM [74].

      Following randomization, DPPOS followed subjects for 15 years and metformin continued to be provided to the group originally assigned to it [75]. Over 15 years of follow‐up, the cumulative incidence of DM was 62% in the placebo group, 56% in the metformin group, and 55% in the intensive lifestyle group. At the end of DPPOS, the aggregate prevalence of microvascular outcomes – which included nephropathy, retinopathy, and neuropathy – did not differ among the 3 treatment groups. However, for women, intensive lifestyle intervention significantly reduced aggregate microvascular disease at 15 years compared to metformin and compared to placebo. Additionally, for those subjects with a baseline BMI ≥ 35 kg/m², the RR for the development of aggregate microvascular disease was significantly lower in the intensive lifestyle intervention group compared to the placebo group. Among participants whose most recent HbA1c was ≥ 6.5%, the intensive lifestyle intervention group showed statistically significant reductions in the aggregate microvascular outcome, retinopathy, and neuropathy compared with placebo and metformin.

      Other benefits of intensive lifestyle changes were seen in DPP subjects [76]. From baseline to year three after randomization, hypertension increased in the placebo and metformin groups but decreased in the intensive lifestyle group. From baseline to year three, dyslipidemia progressed in all three groups but the progression was less in the intensive lifestyle group compared to the metformin and placebo groups. After a mean follow‐up of 3.2 years in the DPP, there were significant improvements in quality of life measures for the intensive lifestyle group, but not for the other two groups [77]. From a payer perspective, 10 years after randomization in DPP, intensive lifestyle changes were cost‐effective, and metformin was marginally cost‐saving compared to placebo [78].

      Da Qing study

      In 1986, a population‐based survey identified subjects in Da Qing, China with IGT [79]. These subjects were then randomized into four groups: control group, diet only, exercise only, and diet plus exercise. At six years post randomization, the mean rate of DM was significantly higher in the control group at 66%, compared to 47% in the diet group, 45% in the exercise group, and 44% in the diet plus exercise group.

The original Da Qing participants were followed for up to 30 years after randomization to assess the effects of intervention of DM incidence, microvascular and macrovascular complications, and mortality [80]. Active intervention occurred for the first six years after randomization until 1992, after which subjects were informed of the study results and asked to continue with normal medical care. No specific interventions were offered after the initial six years, and the three intervention groups were combined into one group for analysis purposes.

      Over the 30‐year follow‐up period, the intervention group had a median delay in DM onset by four years (NNT 10) compared to the control group and a significantly lower cumulative incidence of DM onset (HR 0.61) [80]. At 30 years, there were 26% fewer CVD events in the intervention group compared to the control group. The difference between the two groups continued to increase over time.

      At 30 years, the incidence of retinopathy was 40% lower in the intervention group than in the control group, and incidence of nephropathy and neuropathy were numerically lower in the intervention group but not significantly different [80]. The median delay of composite microvascular disease outcome was 5.2 years in the intervention group (NNT 10). Cardiovascular and all‐cause mortality were also significantly lower in the intervention group (25.6% and 35.2%, respectively) than in the control group (45.5% and 56.3%, respectively). The median delay in CVD death and all‐cause mortality in the intervention group were 7.3 years and 4.8 years, respectively, with NNT of 10 for both outcomes.

      Pharmacologic therapy for the prevention or delay of diabetes mellitus

      A systematic review that included 20 randomized controlled trials examined the efficacy of metformin for the prevention or delay of DM [81]. The overall conclusion was that for at‐risk subjects, metformin compared with placebo reduced or delayed the risk of progression to DM. The incidence of DM was not significantly different when comparing metformin plus intensive diet and exercise and identical intensive diet and exercise alone.

      In addition to metformin, other medications have proven efficacy in reducing progression to DM. Once‐daily subcutaneous liraglutide 3.0 mg as adjunct therapy to lifestyle modifications reduced progression to DM compared to placebo after 160 weeks [82]. In adults with

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