The United States faces a significant public health challenge with one in three adults living with prediabetes [1
], a population at increased risk for progression to type 2 diabetes [2
]. Patients with prediabetes often live with obesity and metabolic syndrome (MetS), each an independent predictor of type 2 diabetes [3
], and the number of comorbidities is associated with increased risk of type 2 diabetes [5
]. Each of these chronic conditions is associated with increased risk of cardiovascular disease, and evidence suggests microvascular damage may be present in patients with prediabetes prior to the development of obvious macrovascular disease. This demonstrates the need to initiate treatment for this high-risk state aimed at reversal of the condition to healthy or lower risk state to prevent or delay the onset of type 2 diabetes.
Intensive lifestyle intervention in the landmark Diabetes Prevention Program (DPP) reduced the incidence of type 2 diabetes by 58% [6
], and use of behavioral interventions like the DPP are recommended by the United States Preventive Services Task Force to reduce risk [7
]. Following the successful translation of the DPP into a community setting [8
], the Centers for Disease Control (CDC) established the National Diabetes Prevention Program (NDPP) to make low-cost lifestyle interventions widely available, and the Centers for Medicare and Medicaid Services (CMS) determined that the NDPP met criteria for expansion to and reimbursement for Medicare participants [9
]. For full CDC recognition and CMS reimbursement, NDPPs must meet specific operational criteria, including 5% average weight loss among participants enrolled at least nine months [10
]. However, retention in these programs is severely challenged. The recent study by Cannon et al. of the NDPP observed only 31.9% retention at 10 months concurrent with a strong association between retention and weight loss [11
]. These findings highlight the imminent need to reconsider the diabetes prevention strategy to ensure that meaningful health improvements are achieved more broadly across this high-risk population [12
We developed an outcomes-driven program, focused on reducing hyperglycemia and normalization of glycemia to delay or prevent the progression to type 2 diabetes, rather than the 5% weight loss goal utilized in the NDPP. This intervention utilized carbohydrate-restricted nutrition therapy delivered through a remotely delivered continuous care model. In this pilot study among 96 patients with prediabetes, we aimed to assess the impact of this alternate approach to type 2 diabetes prevention on retention, adherence, and change in the metabolic condition status of prediabetes and related comorbidities over two years.
These results demonstrate the potential utility of an alternate approach to type 2 diabetes prevention, carbohydrate restricted nutrition therapy delivered through a continuous remote care model, for reversion of prediabetes and improvement of related comorbidities. Seventy-five percent of participants were retained in the program for two years, with an estimated cumulative incidence of normoglycemia of 52% and of progression to type 2 diabetes of 3%. Prevalence of MetS, class II and III obesity, and suspected hepatic steatosis within this cohort significantly declined.
Retention in the present investigation was 80% and 75% at one and two years, respectively, far exceeding the 32% at 10 months [11
] and 13.2% at one year [23
] published in two different analyses of the NDPP. A number of factors may contribute to the differences observed. A remote delivery method may facilitate higher retention, as observed in another virtually delivered intervention [24
]. Other factors include continuous access to a remote care team for support, daily focus on blood BHB goals rather than weight, and the magnitude of mean weight loss (12.7%) achieved in the first year. A relationship between weight loss and retention has been observed in both the NDPP and commercial weight loss programs [11
]. Greater weight loss in the first year was associated with long-term weight loss maintenance of 5% or more, regardless of initial treatment, throughout the DPP and DPPOS [26
Among participants in the present intervention, 64% and 53% achieved the ≥5% weight loss goal established by the CDC at one and two years, respectively, exceeding the 36% observed in the NDPP [23
]. Nearly half of participants in the present study maintained ≥7% weight loss at two years, similar to the 24-week findings of the DPP, which declined to 38% at an average of 2.8 years follow-up [6
]. Given the tendency for weight regain commonly observed across weight loss interventions, long-term retention and greater early weight loss in programs may play a critical role in helping participants maintain improved health status.
Achieving the 5% weight loss goal through a low fat, low calorie diet and physical activity goals has been the cornerstone of the NDPP given the relationship between weight loss and reduced risk of progression to type 2 diabetes in the DPP [27
]. However, transient regression to normoglycemia in the first three years of the DPP was associated with significantly lower risk of progressing to type 2 diabetes during the 6–7 years of follow-up during the DPP Outcomes Study (DPPOS) [28
]. The estimated cumulative incidence of reversion to normoglycemia (52%) in this study exceeded the approximately 35% observed at two years with intensive lifestyle intervention in the DPP [28
]. Relatedly, incidence of progression to type 2 diabetes was low at 1.5 cases per 100 person-years, relative to 4.8 and 7.8 cases per 100-person years observed in the DPP lifestyle intervention and metformin groups [6
]. These findings indicate that alternative short-term targets focused on normalization of glycemia, such as through dietary carbohydrate restriction, may provide viable alternatives to short-term diet and physical activity targets and longer-term weight loss (and weight loss maintenance) goals for diabetes prevention.
Reversion to normoglycemia is associated with positive health benefits beyond type 2 diabetes prevention or delay. Risk of cardiovascular disease, myocardial infarction, stroke, and all-cause mortality was reduced in a Chinese cohort of patients with prediabetes who reverted to normoglycemia within two years compared to those who progressed to type 2 diabetes over nearly nine years of follow-up [29
]. In the DPPOS, achieving transient regression to normoglycemia also reduced odds of developing aggregate microvascular disease (retinopathy, nephropathy, and neuropathy), as well as retinopathy and nephropathy individually [30
]. Prevalence of microvascular complications among the three DPP groups (lifestyle, metformin, and placebo) was similar at 15-years post-randomization as mean HbA1c across the groups converged to within 0.3% and above 6.0%, but prevalence of microvascular complications was 28% lower among those who did not progress to type 2 diabetes compared to those who did [31
]. This may suggest a key role for long-term maintenance of normoglycemia or prevention of progression to type 2 diabetes for maximum benefit. Considering the high rates of retention and normalization of glycemia observed in this study combined with the remote delivery and monitoring methods utilized, this intervention may have the potential to address a critical need in this high-risk population, and future research should assess its long-term effects on prevention of type 2 diabetes and its complications.
Although meeting a particular weight loss target was not a stated goal for participants in this intervention, the majority of enrolled participants met the 5% benchmark at two years. Lifestyle intervention independent of weight loss predicted regression to normoglycemia in the DPP [32
], and hyperglycemia can be resolved prior to significant weight loss following bariatric surgery [33
]. Further, carbohydrate restriction in the absence of weight loss has been demonstrated to reverse metabolic syndrome [34
]. Taken together, this may suggest that weight loss can be an effect of metabolic health improved by other means, rather than a primary driver, further highlighting the potential for alternate goals related to the ultimate outcome of diabetes prevention.
Accompanying normalization of glycemia and weight loss, prevalence of MetS and suspected hepatic steatosis declined following this intervention. Reduction in the prevalence of MetS (−45%) exceeded that of the DPP, where prevalence declined from 51 to 43% [35
] and was similar to a four-week low-carbohydrate feeding study [34
], which demonstrated that MetS resolution is possible with carbohydrate restriction even in the absence of weight loss. Similarly, a study in patients with NAFLD demonstrated that liver fat was reduced significantly following just one day of consuming a ketogenic diet due to reduced de novo lipogenesis and increased beta oxidation [36
], providing a potential explanation for the decreased prevalence of suspected hepatic steatosis observed in this study. The inverse trend in some biomarkers between one and two years is of unknown significance given the significant improvement maintained at two years compared to baseline and existing evidence demonstrating that even transient normalization of glucose can have long-term positive health benefit.
Strengths of this study include its two-year follow-up period and assessment of incident type 2 diabetes, which is lacking in the NDPP. Limitations include the predominance of females enrolled in the study (although this is similar to enrollment in the NDPP), the lack of racial diversity, and that the study was not designed to test the contribution of each component of the intervention to outcomes, nor to evaluate equivalence or superiority to alternate interventions or care models. Data were analyzed conservatively according to intent-to-treat principles and included participants who did not fully adhere to the intervention components; thus, these outcomes are likely to reflect what might be expected in a real-world setting.
As observed in the DPP, clinical outcomes are often tied to program retention and adherence, but focus should remain on achieving and sustaining clinically meaningful outcomes. Historically in the context of prediabetes, outcomes have focused on a 5% weight loss goal through adhering to a low fat, low calorie diet and physical activity targets, but evidence now demonstrates that metabolic health can be improved by focusing on alternate targets, such as achievement of normoglycemia through nutrition therapy. Remote delivery methods may provide another strategy for improving retention and facilitating improved health outcomes in a larger proportion of individuals.