This study evaluated the effectiveness and safety of an alternative treatment model for T2D that utilized continuous remote care to provide a high level of outpatient support combined with individualized nutrition enabling long-term maintenance of behavioral and metabolic change via nutritional ketosis. This trial prospectively observed adults with T2D undergoing treatment via this novel care model and a comparison group of adults with T2D undergoing usual care treatment. Following 1 year of CCI, participants achieved a 14 mmol mol−1 (1.3 ± 0.1%) decline in HbA 1c concurrent with 12% weight loss and reduction in medication use. Consistent conclusions were reached with intention-to-treat analysis and analysis of completers. A usual care group showed no change in diabetes status or related biomarkers over the year.

Effectiveness

The CCI reduced HbA 1c by 14 mmol mol−1 (1.3%) at 1 year. HbA 1c reductions up to 7 mmol mol−1 (0.6%) via intensive lifestyle intervention [25] and 11 mmol mol−1 (1.0%) via an energy-restricted low-carbohydrate diet with partial food provision delivered via an outpatient setting [26] were previously reported. The present intervention achieved 12% weight loss at 1 year; previously studied interventions elicited 4–9% weight loss in patients with T2D [25, 26]. The regular monitoring of weight, glucose, and BHB as biometric feedback for participant, health coach, and medical provider may have provided behavior reinforcement. Further, it seems plausible that this multicomponent care model allowed for greater improvements compared to interventions that provided a subset of components. A recent primary care-led weight management intervention utilizing a 3–5 month VLCD resulted in a 10 mmol mol−1 (0.9%) reduction in HbA 1c and 10% weight loss at 1 year; 46% of participants achieved HbA 1c below 48 mmol mol−1 (< 6.5%) while taking no medications [27]. While only 25% of participants in the present investigation achieved this measure of diabetes remission, the protocol for the present investigation discontinued metformin prescription only because of contraindication, intolerance, or patient request given its efficacy for T2D prevention and recommended use in certain populations [7]. An additional 35% of participants in the present investigation were able to attain HbA 1c below 48 mmol mol−1 (< 6.5%) while taking only metformin. The longer duration of T2D and baseline insulin prescription to 30% of participants might be factors influencing the proportion of participants in which glycemic control medications could be discontinued in this investigation.

HbA 1c improved concurrent with medication reductions prescribed for blood glucose-lowering. For each medication class, the sum percentage of eliminations and reductions of prescriptions at 1 year exceeded that observed at 70 days [23]. Improved glycemic control via a predominantly pharmaceutical approach has demonstrated paradoxical increased cardiovascular risk [28]. Tight glycemic control can elicit symptomatic hypoglycemia [29] or weight gain [30], neither of which was observed in CCI. Thus, it is likely the treatment method by which glycemic control is achieved (e.g., pharmacological, surgery, lifestyle intervention) is important to health outcomes and risk.

Most changes in HbA 1c , glucose, insulin, C-peptide, and HOMA-IR occurred in the first 70 days with further improvement observed at 1 year. While the mechanism for improved insulin sensitivity in ketosis is not fully understood, early improvements in HbA 1c and HOMA-IR indicate rapid restoration of liver and peripheral insulin sensitivity and are consistent with improvements observed within 2 weeks of ketosis when measured by euglycemic hyperinsulinemic clamp [13]. Utilization of blood BHB for self-monitoring with reinforcement by clinicians may have contributed to sustained HbA 1c improvement. Further, BHB acts as a signaling molecule, reducing inflammation and oxidative stress [14, 15]; therefore, mild ketonemia may benefit multiple organs and systems. With appropriate dietary formulation, benefits of nutritional ketosis are observed in mouse models of longevity and health span [31, 32]. Participant mean BHB levels are of similar magnitude to those observed with SGLT-2 inhibitor treatment (~ 0.5 mmol L−1) [33]. Recent trials [5, 34] demonstrate cardiovascular benefits to two SGLT-2 inhibitors; mild ketosis was postulated as a mechanism [33]. Nutritionally achieved ketosis may have long-term cardiovascular benefits without the pharmaceutical risk profile [34]. Further, presence of glucose and palmitate has been associated with beta cell apoptosis [35]. Given the reduced levels of glucose and palmitate observed during nutritional ketosis [36], it is plausible that ketosis might play a role in attenuating glucolipotoxicity-induced beta cell death.

Beyond achieving improved glycemic control concurrent with medication and weight reductions, the CCI had broad positive impact on blood pressure, liver enzymes, hsCRP, triglycerides, and HDL-C. Elevated ALT, AST, and ALP are associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis [37]; these enzymes were significantly reduced with intervention. Rapid reduction in triglycerides and gradual rise in HDL-C observed following CCI are consistent with previously studied carbohydrate-restricted interventions and carbohydrates are well known to increase triglycerides [38]. Of the 108 CCI completers with elevated baseline triglycerides (≥ 1.69 mmol L−1), 54% were in normal range at 1 year. Rise in LDL-C at 1 year, occurring with significant triglyceride decrease, was expected as there is less exchange via cholesteryl ester transfer protein [39]. However, this exchange would not affect particle number and ApoB was unchanged, suggesting an overall neutral impact on LDL lipoprotein-associated cardiovascular risk. In epidemiological studies, utilization of dietary saturated fat in place of carbohydrate was associated with beneficial impact on lipid profile, cardiovascular outcomes, and mortality despite higher LDL-C [40, 41]. Transiently increased total and LDL cholesterol were also associated with mobilization of adipose cholesterol stores during major weight loss [42].

Consistent with population-level studies that observed very low rates of diabetes remission [43], the UC group had no change in HbA 1c and other indicators of glycemic status and insulin resistance but a net increase in diabetes medication use. Laboratory tests were generally unremarkable with biomarkers not changing significantly. The same facilities and methodologies were used for both the CCI and UC participants indicating that the changes observed in CCI participants not observed in the UC participants are unlikely to be due to methodological changes in clinical or laboratory data capture.

Despite independent recruitment of the CCI and UC groups, most of their baseline characteristics including HbA 1c and years since diabetes diagnosis were not significantly different. To enable a comparison between the CCI and UC groups, covariate adjustment was utilized to adjust for differences in baseline characteristics including sex, age, baseline BMI, baseline insulin use (user vs. non-user), and African-American race. With or without baseline adjustment, the change over 1 year elicited in the CC and UC groups differ in all primary outcomes—HbA 1c , medication use, and weight—and most secondary outcomes including lipid profile, inflammation, and liver function. In general, the favorable changes observed in the CCI were not observed in the UC cohort. For example, of patients who obtained HbA 1c measurements at 1 year, 60% of CCI participants achieved a HbA 1c below 48 mmol mol−1 (< 6.5%) while taking no diabetes medications or metformin only, whereas only 10% of UC participants achieved this status.

One interpretation of these results is that the differences in observed outcomes over the year are due to advantages of the CCI over usual care. This suggests a need to incorporate carbohydrate restriction and comprehensive, continuous remote care as options in current guidelines for patients with diabetes as evidence accumulates [44]. However, alternative explanations are possible that may account for the large degree of difference observed. For instance, patients entering the CCI were recruited knowing that they were making a commitment to lifestyle change, while the UC participants were identified as recent referrals to local diabetes education programs and may not have had similar motivation or expectations of effort as the CCI participants. However, even when motivation is controlled for upon recruitment as an inclusion criterion for participation, additional factors may play a role in retention as evidenced by a recent study with randomization [45]. Also, the CCI and UC cohorts may also have differed in baseline characteristics that were not captured such as socioeconomic status.

Additionally, the treatment intensity of the two cohorts was not equal. The UC participants had one or more meetings with a registered dietitian and were under the medical supervision of their primary care provider or endocrinologist with periodic medical visits. In contrast, the CCI participants received a comprehensive and individualized continuous remote care intervention (and in one subgroup, the addition of on-site group classes). A more intensive intervention might have delivered somewhat better results than the investigation’s UC group. For instance, a recent in-person group-based intervention for weight loss in T2D adults reduced HbA 1c by 3 mmol mol−1 (0.3%) and weight by 4.0% after a year and medications were reduced in 26% of participants [46]. Future research might compare interventions of similar intensity with different treatment strategies to begin to understand the contribution of each component of the intervention to the overall effect.

Adherence to CCI

Eighty-three percent of CCI participants were retained through 1 year; patient perceived benefits of favorable health outcomes, individualized continuity of care, relationship with health coach, ongoing education, biometric feedback, and peer support may have aided retention. Most participants achieved nutritional ketosis during CCI and maintained elevated BHB at 1 year, indicating sustainability and was possibly enabled by the novel use of blood BHB as daily biofeedback for adherence.

Safety of CCI

No episodes of ketoacidosis, no hypo- or hyperglycemic events requiring assistance, and no adverse events were attributable to the CCI. With improvements or no change in liver, kidney, and thyroid function, safety of the intervention appears favorable. The absence of hypoglycemic events requiring assistance despite relatively tight glucose control may be due to the careful medical provider prescription management, especially rapid downward titration of insulin and sulfonylurea preventing hypoglycemia following dietary changes. Additionally, elevated BHB may have offered protection against hypoglycemic events, as starvation-adapted humans with elevated BHB have demonstrated full preservation of central nervous system function despite profound hypoglycemia induced by exogenous insulin [47].

Study Strengths and Weaknesses

Prior studies have demonstrated favorable improvements in T2D status following carefully managed ketogenic diets as case series [48] or in small short-term randomized trials [45]. This study’s strengths include its prospective design, large cohort, high retention, duration, replication of findings between the CCI-onsite and CCI-web groups, and the collection of multiple time points in the intervention group allowing assessment of how biomarkers changed over time. This study also included participants prescribed insulin and with long-standing T2D, which were often exclusion criteria for prior studies. The means of recruitment, outpatient setting, and lack of food provision may enhance the real-world application of this study.

Weaknesses of this study include that it occurred at a single site and participants were mostly Caucasian. Socioeconomic and psychosocial status and genetics data were not collected. The study was not of sufficient size and duration to measure hard endpoints (e.g., mortality). Future trials could include a multi-site randomized controlled trial with greater racial and ethnic diversity, broader age range, and greater disease severity.