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Type 2 diabetes (T2D) is typically managed with a reduced fat diet plus glucose-lowering medications, the latter often promoting weight gain.
We evaluated whether individuals with T2D could be taught by either on-site group or remote means to sustain adequate carbohydrate restriction to achieve nutritional ketosis as part of a comprehensive intervention, thereby improving glycemic control, decreasing medication use, and allowing clinically relevant weight loss.
This study was a nonrandomized, parallel arm, outpatient intervention. Adults with T2D (N=262; mean age 54, SD 8, years; mean body mass index 41, SD 8, kg·m−2; 66.8% (175/262) women) were enrolled in an outpatient protocol providing intensive nutrition and behavioral counseling, digital coaching and education platform, and physician-guided medication management. A total of 238 participants completed the first 10 weeks. Body weight, capillary blood glucose, and beta-hydroxybutyrate (BOHB) levels were recorded daily using a mobile interface. Hemoglobin A1c (HbA1c) and related biomarkers of T2D were evaluated at baseline and 10-week follow-up.
Baseline HbA1c level was 7.6% (SD 1.5%) and only 52/262 (19.8%) participants had an HbA1c level of <6.5%. After 10 weeks, HbA1c level was reduced by 1.0% (SD 1.1%; 95% CI 0.9% to 1.1%,
These initial results indicate that an individualized program delivered and supported remotely that incorporates nutritional ketosis can be highly effective in improving glycemic control and weight loss in adults with T2D while significantly decreasing medication use.
Type 2 diabetes is generally regarded as a chronic, progressive disease that can be slowed by the vigorous use of lifestyle changes and medications but eventually results in vascular damage and end-organ failure [
Despite the overall paucity of type 2 diabetes remission data, there exist three notable treatment exceptions. Bariatric surgery, such as gastric bypass, is effective at reversing type 2 diabetes, with 40%-60% of surgical patients demonstrating remission 1 year after the surgery. The most comprehensive study of surgical intervention to prevent or reverse type 2 diabetes is the Swedish Obese Subjects Trial [
There have been many reports of short-term improvement in glycemic control with very low-calorie diets (VLCDs) consisting of either common foods or chemically defined formulas, ranging in energy from 400-800 kcal·day−1. Bistrian et al [
These 4 studies [
Alternatively, nutritional ketosis, defined as a dietary regimen resulting in serum beta-hydroxybutyrate (BOHB) levels between 0.5 and 3.0 mmol·L−1 [
There have been a number of studies using low-carbohydrate, high-fat dietary strategies in the management of type 2 diabetes [
We therefore hypothesized that a comprehensive program with individualized nutritional recommendations that supports participants in achieving sustained nutritional ketosis while eating to satiety may have unique benefits in the management of type 2 diabetes. Specifically, this study was designed to assess the practical utility of an intensive digital intervention supported by medical management, continuous digital health coaching, nutrition education, behavioral support, biometric feedback, and peer support via an online community. We refer to this technology-enabled medical service as the Virta Clinic.
Adults with type 2 diabetes between the ages of 21 and 65 years were recruited via clinical referrals, media advertising, and word of mouth in the greater Lafayette, Indiana, region. Exclusion criteria included advanced renal, cardiac, and hepatic dysfunction, history of ketoacidosis, dietary fat intolerance, or pregnancy or planned pregnancy.
Virta utilizes a technology-enabled, full-service clinic model for metabolic recovery from type 2 diabetes including medical management by physicians, health coaching, nutrition and behavior change education, biometric feedback, and peer support. Physicians and health coaches were trained in the basic principles of achieving and maintaining nutritional ketosis based on previous published works [
Remote support was provided to each subject through tracking of daily biometrics, the assignment of a personal health coach available daily via one-on-one texting for advice and problem solving, support via an online community of his or her peers, and physician supervision. Subjects were instructed to monitor and report glucose level via the Web to the care team 1-3 times per day, and a physician made medication changes as appropriate. Additionally, the medication status of each participant was reviewed by the care team and the principal investigator weekly.
The Virta Clinic includes individualized nutritional recommendations to sustain nutritional ketosis by titrating carbohydrate and protein intake to the patient’s individual tolerance [
Type 2 diabetes status was determined by HbA1c level at baseline and again at 10-11 weeks into the program. A value of 6.5% or greater, or HbA1c level <6.5% but taking at least one hypoglycemic medication, was considered indicative of type 2 diabetes. Secondary outcome measures included assessment of (1) body weight determined daily on a cellular-connected scale (BodyTrace BT003 cellular-connected scale, New York, New York, USA); (2) medication use for control of diabetes; and (3) blood pressure obtained in the seated position. Fasting blood was analyzed for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, total white blood cell count, and kidney and liver functions. All laboratory test results were analyzed by standard procedures. Hunger was assessed using a 4-point Likert scale from 1 (no) to 4 (always), representing the participant’s subjective level of hunger over the previous 24-hours.
Descriptive statistics were calculated for each variable as mean (SD). Baseline and 10- to 11-week follow-up measures were compared with paired-sample
The protocol was reviewed and approved by the Institutional Review Board at Franciscan Health Lafayette East, Lafayette, Indiana. Subjects were informed of the purpose and possible risks of the investigation before signing an informed consent document approved by the institutional review board.
A total of 262 subjects with diagnosis of type 2 diabetes were enrolled in this study. The mean age was 54 (SD 8) years and 66.8% (175/262) were female. Additional baseline data are provided in
Participant characteristics at baseline and follow-up.
Characteristics | na | Baseline | Follow-up | Mean difference | |||||||
Mean (SD) | Mean (SD) | Mean (SD) | 95% CI | ||||||||
All | 262 | 7.6 (1.5) | 6.6 (1.1) | −1.0 (1.1) | −1.1 to −0.9 | 14.9 | <.001 | ||||
Completers | 238 | 7.6 (1.5) | 6.5 (1.0) | −1.1 (1.1) | −1.2 to −1.0 | 15.6 | <.001 | ||||
All | 259 | 162 (61) | 131 (37) | −30 (56) | −37 to −25 | 8.68 | <.001 | ||||
Completers | 236 | 163 (62) | 129 (34) | −33 (58) | −41 to −26 | 8.8 | <.001 | ||||
All | 262 | 40.8 (8.9) | 37.9 (8.5) | −2.9 (1.2) | −3.1 to −2.7 | 30 | <.001 | ||||
Completers | 238 | 40.7 (8.5) | 37.7 (8.0) | −3.1 (1.5) | −3.3 to −2.9 | 31.3 | <.001 | ||||
All | 262 | 117 (26.3) | 109 (24.9) | −8 (4.6) | −9 to −8 | 29.1 | <.001 | ||||
Completers | 238 | 117 (25.7) | 109 (24.3) | −9 (4.5) | −9 to −8 | 30.7 | <.001 | ||||
All | 260 | 132 (16) | 126 (15) | −6 (19) | −8 to −4 | 5.29 | <.001 | ||||
Completers | 236 | 132 (17) | 125 (15) | −7 (20) | −9 to −4 | 5.32 | <.001 | ||||
All | 260 | 82 (10) | 78 (10) | −4 (12) | −5 to −2 | 5.22 | <.001 | ||||
Completers | 236 | 82 (10) | 78 (9) | −4 (12) | −6 to −3 | 5.25 | <.001 | ||||
All | 262 | 177 (41) | 172 (41) | −5 (31) | −9 to −1 | 2.64 | .009 | ||||
Completers | 238 | 177 (41) | 172 (41) | −6 (33) | −10 to −1 | 2.64 | .009 | ||||
All | 245 | 97 (33) | 99 (36) | 2 (25) | −2 to 5 | 0.987 | .32 | ||||
Completers | 223 | 98 (34) | 99 (37) | 2 (27) | −2 to 5 | 0.987 | .32 | ||||
All | 262 | 44 (13) | 44 (13) | 0.5 (8) | −0.5 to 1 | 0.966 | .33 | ||||
Completers | 238 | 44 (14) | 45 (13) | 0.5 (8) | −0.5 to 1.5 | 0.966 | .33 | ||||
All | 262 | 185 (127) | 147 (87) | −37 (107) | −50 to −24 | 5.61 | <.001 | ||||
Completers | 238 | 185 (129) | 145 (84) | −41 (112) | −55 to −27 | 5.64 | <.001 | ||||
All | 259 | 0.88 (0.24) | 0.85 (0.22) | −0.03 (0.12) | −0.04 to −0.01 | 3.61 | <.001 | ||||
Completers | 236 | 0.88 (0.24) | 0.85 (0.22) | −0.03 (0.13) | −0.05 to −0.01 | 3.61 | <.001 | ||||
All | 259 | 31 (23) | 26 (16) | −4 (19) | −7 to −2 | 3.82 | <.001 | ||||
Completers | 236 | 31 (24) | 26 (16) | −5 (20) | −7 to −2 | 3.83 | <.001 | ||||
All | 259 | 24 (15) | 21 (9) | −3 (13) | −4 to −1 | 3.31 | <.001 | ||||
Completers | 236 | 24 (16) | 21 (9) | −3 (14) | −5 to −1 | 3.31 | <.001 | ||||
All | 259 | 74 (22) | 68 (20) | −6 (11) | −8 to −5 | 9.78 | <.001 | ||||
Completers | 236 | 75 (22) | 67 (20) | −8 (11) | −9 to −6 | 9.96 | <.001 | ||||
All | 247 | 8.1 (8.2) | 9.2 (11.5) | 1.2 (7.5) | −0.2 to 2.1 | 2.45 | .01 | ||||
Completers | 225 | 8.2 (8.1) | 9.6 (12.1) | 1.4 (8.1) | −0.3 to 2.1 | 2.6 | .01 | ||||
All | 236 | 7.2 (1.9) | 6.7 (1.9) | −0.5 (1.3) | −0.6 to −0.3 | 5.37 | <.001 | ||||
Completers | 234 | 7.2 (1.8) | 6.7 (1.9) | −0.5 (1.3) | −0.6 to −0.3 | 5.36 | <.001 |
aReductions in the number of participants (n) are due to missed laboratory orders, except in the case of LDL-C, where LDL-C was incalculable.
bWe set
cLDL-C: low-density lipoprotein cholesterol.
dHDL-C: high-density lipoprotein cholesterol.
eALT: alanine aminotransferase.
fAST: aspartate aminotransferase.
gWBC: white blood cell.
At 11 weeks, 21 of the 262 subjects had dropped out and 3 had not obtained the follow-up laboratory test results, yielding 238 or 90.8% retention for this phase of the study. Among the noncompleters, the most common reasons to leave the study were as follows: removed for noncompliance (n=6), unrelated health issue took priority (n=3), family illness or other issues (n=3), cost of medical appointments (n=2), and undisclosed personal choice (n=2). The age and sex distributions did not differ between noncompleters and completers.
Daily BOHB level averaged over 10 weeks of the program was 0.6 (SD 0.6) mmol·L−1 (see
Relative frequency distribution of participant weekly average beta-hydroxybutyrate (BOHB) concentrations. An observed weekly average BOHB concentration on the border of 2 bins is placed in the bin holding the larger values. Evidence of carbohydrate restriction exhibited by elevated ketones was present in the first week in the majority of subjects and maintained for the duration of the study. All reported BOHB concentrations greater than 3.0 were in participants taking a sodium-glucose cotransporter-2 inhibitor, except for one (4.4 mmol•L−1) in which we suspect elevated BOHB due to increased exercise and another (6.0 mmol•L−1) in which we suspect participant data entry error. Excluding this 1 value, average BOHB concentrations for this participant ranged from 0.4 to 1.4 mmol•L−1.
Baseline HbA1c level was 7.6% (SD 1.5%) and 210/262 (80.2%) participants had an HbA1c level of ≥6.5%. After 10 weeks, HbA1c level was reduced by 1.0% (SD 1.1%; 95% CI 0.9% to 1.1%,
Post hoc analysis of method of educational content delivery revealed there was no significant interaction between delivery method and time for HbA1c (
Hemoglobin A1c (HbA1c) changes by baseline level. Error bars represent SD; the dotted line represents the threshold for diagnosis of type 2 diabetes. Significant reductions in HbA1c level from baseline to follow-up were observed in subjects whose baseline HbA1c level was ≥7.5% (mean 9.0%, SD 1.3% to 7.2%, SD 1.1%,
The majority of participants (234/262, 89.3%) were taking at least one diabetes medication at baseline. Both the number and dosage of most diabetes medications were reduced substantially in the first 10-11 weeks of the Virta Clinic program (
Change in prescription of medication class or dose between baseline and follow-up.
Change in medication prescription or dose between baseline and follow-up | n | HbA1ca <6.5% at follow-up, |
Baseline HbA1c (%), |
Follow-up HbA1c (%), |
Increase | 13 | 4 (31) | 8.5 (2.0) | 7.4 (1.4) |
No change | 88 | 57 (65) | 7.2 (1.2) | 6.5 (1.0) |
Decrease | 112 | 47 (42) | 8 (1.6) | 6.8 (1.1) |
Complete elimination of medications | 21 | 17 (81) | 6.7 (0.9) | 6.1 (0.5) |
No medications prescribed | 28 | 22 (79) | 7.3 (1.3) | 6.3 (1.1) |
aHbA1c: hemoglobin A1c.
Frequency of medication dose changes by drug class. Bars represent total users of each drug with the type of dose change (increase, no change, decrease, or elimination) stacked within the bar and the relative frequency noted next to each section. The total number of users is noted at the top of each bar. The proportion of participants who were prescribed the drug was significantly different between baseline and follow-up for insulin (χ21=21.4,
Hemoglobin A1c (HbA1c) level at baseline and 10-11 weeks per change in insulin dosage. Insulin users who were able to eliminate or reduce their use of the drug also significantly reduced their HbA1c level (7.9%, SD 1.5%, to 6.6%, SD 0.9%, P<.001 and 8.8%, SD 1.8%, to 7.4%, SD 1.2%, P<.001, respectively). Six users with no change in insulin dose achieved a reduction in HbA1c level, although it was not statistically significant (8.2%, SD 1.8%, to 7.6%, SD 1.2%, P=.25). Despite an increased insulin dosage in 4 users, HbA1c level increased but the difference was not significant (8.3%, SD 0.4%, to 8.7%, SD 0.8%, P=.61).
Weight and body mass index (BMI) changes from baseline to 10 weeks are presented in
Participant weight loss over 10 weeks. Part “a”—weight change over 10 weeks for all participants. Solid line represents the mean; dotted lines represent one standard deviation from the mean. Part “b”—individual body weight changes as percentage of starting body weight at 10 weeks for completers (n=238). Part “c”—individual body weight changes as percentage of starting body weight for each noncompleter at the time of removal from study. For the 21 dropouts, time to drop out was 6 (SD 3) weeks (n=3 participants are still enrolled in the study but did not complete 10-week follow-up testing).
Consistent with the HbA1c changes, the fasting glucose level (
Baseline hunger on a scale from 1 (no) to 4 (always) was 1.6 (SD 0.6). At 10 weeks, subjective hunger was 1.3 (SD 0.4; 95% CI of mean difference: −0.4 to −0.2,
One subject withdrew from the study in the first 70 days because of a dietary side effect (diarrhea due to fat intolerance). There were no serious adverse events in this time period and, specifically, no serious symptomatic hypoglycemic events requiring medical intervention.
Although the American Diabetes Association has recently relaxed its advocacy for severe dietary fat restriction, the current paradigm for the management of type 2 diabetes is to prescribe a diet containing about 40% of energy from carbohydrates (eg, a Mediterranean diet) and then adjust medications as necessary to maintain glycemic control [
Other group-based and digitally delivered programs have demonstrated improvements in HbA1c level with modest or no reduction in weight and often without a reduction in medication. A recent in-person group-based intervention for weight loss in adults with type 2 diabetes reduced HbA1c level by 0.7% and weight by 3.3% after 12-13 weeks [
Achieving an HbA1c value under 6.5% is considered “tight control” for type 2 diabetes. There are two commonly reported side effects of tight control—weight gain [
As it pertains to weight loss, it is all the more interesting that the Virta Clinic instructs its participants to strictly limit carbohydrates and eat protein in moderation but to eat fat to satiety. In daily Web-based questionnaires, patients reported reduced hunger once adapted to the ketogenic diet. This subjective decrease in hunger, albeit modest in magnitude, may have allowed the majority of subjects to experience significant weight loss. This concurrent combination of weight loss and reduced hunger is particularly interesting given that significant weight loss by caloric restriction typically increases hunger [
Although we have not calculated the economic implications of improved glycemic control with reduced medications, the removal of diabetes medications combined with clinically significant weight loss [
In conclusion, we demonstrated for the first time that biomarkers of type 2 diabetes can be reversed in a substantial fraction of participants using a comprehensive digitally delivered intervention, including medical management by physicians, health coaching, nutrition education emphasizing individualized carbohydrate intake to induce nutritional ketosis, behavioral support, biometric feedback, and peer support. In contrast to current intensive pharmaceutical management strategies, the positive results were achieved with less use of medication and substantial weight loss. The brief duration of this initial study cannot predict the long-term outcomes or sustainability of the nutrition recommendations used by the Virta Clinic. Early results demonstrate markedly improved glycemic control with less medication and modest changes in blood pressure, total white blood cell count, and liver and kidney functions. Ongoing work will evaluate the efficacy and sustainability of this intervention over 2 years.
body mass index
beta-hydroxybutyrate
hemoglobin A1c
very low-calorie diet
The authors would like to acknowledge Tamara Hazbun MD, Monica Keyes FNP, Nasir Bhanpuri PhD, Sydney Rivera, Deklin Veenhuizen, Hans Chiang, and Rachel Bolden for medical management and technical assistance. We also gratefully acknowledge the dedicated participation of our subjects. This study was funded by Virta Health Corp.
Virta Health Corp. funded this study, and all authors have a financial relationship with the study sponsor. ALM, SJH, BCC, BMV, TML, MKA, RMG, JPM, and SJP are employed by Virta. JSV serves as a consultant to Virta. JSV and SDP are cofounders of Virta. All authors have stock options in Virta. The organization contributed to study design, the collection, analysis, and interpretation of data, and approval of the final manuscript. Potentially related conflicts of interest are as follows: SDP serves as a consultant to Atkins Nutritionals and has received royalties as an author of two science-based low-carbohydrate books published by Beyond Obesity LLC. JSV serves as a consultant to Atkins Nutritionals, Metagenics, and UCAN, has received grants from the National Dairy Council and Malaysian Palm Oil Board, and has received royalties as an author of two science-based low-carbohydrate books published by Beyond Obesity LLC. SJH serves as a consultant to Atkins Nutritionals.