Table 2.

Type 2 Diabetes Interventions With Therapeutic Dosing.

First author, publication year (ref), study design/study duration (months)/study population	Total enrolled/analyzed [F%]; N, baseline mean age (SD or SE), and mean BMI (SD or SE)	Intervention treatment	Control treatment	Remission definition	Remission rate and weight loss (kg) or change in BMI (kg/m2)	Dosing effectiveness comments
Lean, 2018,22* and 2019,17** Diabetes Remission Clinical Trial (DiRECT), cluster-randomized trial Duration: 12 months, with 24 month follow-up UK, adults 20-65 years, type 2 diabetes ≤6 years, BMI 27-45 kg/m2 6% < HbA1c < 12%; weight loss <5 kg in past 6 months, and not receiving insulin. Other comorbidities were excluded If HbA1c <6.5%, participants must be on antidiabetic medication *Intervention, baseline, and 12-month results data extracted from 2018 paper. **2-year follow-up results extracted from 2019 paper.	298/290 [90%]—12 months 298/272 [91.3%]—24 months Intervention N = 142 Age mean (SD) 52.9 (7.6) years 35.1 (4.5) kg/m2 Control N = 148 Age mean (SD) 55.9 (7.3) years 34.2 (4.3) kg/m2	Evidence-based weight management program (Counterweight-Plus) with aim to reach and maintain at least 15 kg weight loss Diet replacement with low energy formula diet (825-853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) for 3-5 months Structured food reintroduction of 2-8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein). Monthly visits for long-term weight loss maintenance Maintain usual PA during meal replacement stage; Step counters and PA strategies during food reintroduction stage, targeting up to 15 000 steps per day.	Standard care using current guidelines and standards from the National Institute of Health and Care Excellence in England and the Scottish Intercollegiate Guidelines Network in Scotland	HbA1c < 6.5% after at least 2 months off all antidiabetic medications	12 months Remission Intervention 46% Control 4% (P < .0001 vs intervention) Weight loss of >15 kg Intervention 24% Control 0% Mean weight loss Intervention 10 kg Control 1 kg (P < .0001 vs intervention) 24 months Remission Intervention 41% Control 3% (P < .0001 vs intervention) Weight loss of >15 kg Intervention 11% Control <1% (P = .0023 vs intervention) Mean weight loss, kg (SD) Intervention 7.6 (6.5) Control 2.3 (5.2) (P < .0001 vs intervention)	This large cluster-randomized clinical trial used intensive energy restriction (825-853 kcal/day). Partial remission (HbA1c <6.5%) was achieved by 46% in the intervention group vs 4% of controls. The rate was 86% in intervention subjects losing >15 kg. The study shows that sufficiently dosed, dietary lifestyle interventions can produce remission in a standard clinical practice setting.
Lim, 2011,23 case-control pilot single-arm intervention, Counterpoint Study Duration: 2 months UK adults age 35-65 years Cases had type 2 diabetes <4 years, HbA1c 6.5% to 9.0%, stable BMI 25-45 kg/m2 Excluded if: • Being treated with thiazolidinediones, insulin, steroids or beta-blockers • Serum creatinine >150 mmol/L • Serum alanine transaminase level >2.5-fold above the upper limit of the reference range • Contraindications for MRI Controls matched for weight, age, and sex. Controls had no family history of diabetes, no medication, and normal glucose metabolism confirmed by standard 75 g OGTT	24/20 [83%] Mean (SD) Intervention (Cases) N = 11 49.5 (2.5) years 33.6 (1.2) kg/m2 Control N = 9 49.7 (2.5) years 33.4 (0.9) kg/m2	8-week intervention period with provided liquid meal replacement diet (46.4% carbohydrate, 32.5% protein, and 20.1% fat; vitamins, minerals, and trace elements [510 kcal/day] Optifast; Nestlé Nutrition, Croydon, UK), plus 3 portions of nonstarchy vegetables (total energy 600 kcal/day) and nutritional counseling. Total energy ~1150 kcal/day Encouraged to drink at least 2 liters energy-free beverages, maintain usual PA. Support via regular telephone contact.	NA—no intervention given	Normalization of beta cell function (assessed by fasting insulin secretion rate) and insulin sensitivity (assessed by suppression of hepatic glucose production by insulin infusion [%])	Remission rate NR but 100% remission presumed at week 8 based on remission definition Beta-cell function: At 8 weeks in intervention group the insulin secretion rate was not significantly different from control (0.46 ± 0.07 vs 0.62 ± 0.15 nmol min-1 m-2; P = .42) Insulin sensitivity: Baseline hepatic insulin sensitivity 43 ± 4% intervention vs 68 ± 5% in control (P = .001) Week 1 produced improvement in hepatic insulin responsiveness—insulin suppression of hepatic glucose production increased to 74 ± 5% (P = .003 vs baseline) Weight loss (BMI NR) Intervention 15.3 ± 1.2 kg Control NR	This small bench study measured all relevant variables associated with T2D and insulin resistance. Dosing was intensive to produce maximum treatment effect (100% of participants normalized beta-cell function insulin sensitivity). Remission rates indicate the intervention was highly effective; comparable to bariatric surgery but without the risks of surgery.
Sarathi, 2017,20 single-arm intervention Duration: 24+ months Asian-Indian young adults newly diagnosed with type 2 diabetes; analysis divided into patients with T2D reversal at 3 months and those without reversal	32/32 [100%] Mean (SD) age at diagnosis: 24.97 (3.81) years; mean (SD) age of patients who achieved reversal: 24.83 (3.34) years; patients with no reversal: 25.37 (2.82) years	Daily calorie intake of 1500 kcal (60% as carbohydrates, 15% as proteins, and 25% as fat) and brisk walking for 1 h every day Subjects with HbA1C ≥9.0% were started on metformin 500-2000 mg; subjects with comorbid conditions requiring early glycemic control were started on insulin followed by oral antidiabetic agents (metformin ± DPP4 inhibitors)	NA	At 3 months, complete reversal = normalization of fasting plasma glucose (<100 mg/dL At 1 year or later, complete remission = normal fasting plasma glucose of <100 mg/dL and HbA1c of <5.7%	Reversal/remission At 3 months: 53.1% At 1 year: 50% At 2 years: 46.9% Weight loss Reversal group: Mean (SD) change in weight 3 months 7.41 (2.1) kg No reversal group: Mean (SD) change in weight 3 months 4.25 (1.16) kg	This small intervention study used modest caloric restriction (total 1500 kcal/day) with moderate exercise (walking 1 h/day) in young adults with newly diagnosed T2D. Complete remission was achieved by 53% at 3 months, and by ~50% at 2 years. Adherence was not reported but weight loss at 3 months was almost twice in those achieving complete remission compared to those without.
Steven, 2015,24 single-arm intervention trial of T2D following Counterpoint Study, participants analyzed comparing diagnosis of short duration (<4 years) or long duration (>8 years) Duration: 8 weeks UK adults age 25-80 years, BMI 27-45 kg/m2, type 2 diabetes treated by diet, metformin, sulphonylureas, dipeptidyl peptidase-4 inhibitors and/or insulin Excluded if: • Recent weight loss >5 kg • Txt w/thiazolidinediones, GLP-1 agonists, steroids, or atypical antipsychotics • HbA1c >9.5% • Serum creatinine >150 µmol/L Alcohol >3 units/day (women) or >4 units/day (men)	30/29 [97%] Mean (SE) Short duration N = 15 52.1 (2.6) years 34.2 (0.8) kg/m2 Long duration N = 14 61.6 (2.0) years 34.3 (1.2) kg/m2	Hypocaloric diet using meal replacement liquid diet formula (43% carbohydrate, 34% protein and 19.5% fat; vitamins, minerals and trace elements; [624 kcal/day]; Optifast; Nestle Nutrition, Croydon, UK), plus consumption of up to 240 g of nonstarchy vegetables per day (total energy (624-700 kcal). Encouraged to drink at least 2 liters energy-free beverages, maintain usual PA. Support via regular telephone contact, e-mail, text, or face-to-face contact. All medications discontinued at the start of the study.	NA	Remission not explicitly defined Study goal was to assess the proportion of short- and long-duration type 2 diabetics who achieved non-diabetic FPG levels (<126 mg/dL) The proportion of participants achieving nondiabetic HbA1c levels was also measured (<6.5%)	Short duration 87% achieved nondiabetic FPG Mean (SE) 5.8 (0.2 mmol/L) Long duration 50% achieved nondiabetic FPG FPG mean (SE) Duration 8-12 years 6.2 (0.7 mmol/L) Duration ≥12 years 10.6 (1.7 mmol/L) Change in BMI Short duration Baseline: 34.1 (0.8) Week 8: 29.1 (0.9) P < .001 Long duration Baseline: 34.3 (1.2) Week 8: 29.4 (1.1) P = .001	This intervention trial achieved partial remission in 87% in those with T2D <4 years and in 50% of those with T2D >8 years
Umphonsathien, 201921, single-arm intervention study Duration: 3 phases 2-week run-in 8-week caloric restriction 4-week caloric transition Thai adults (age 20-60) with obesity (BMI of 23-30 kg/m2) and T2D for <10 years	20/19 [95%] 48 (1.7) years BMI mean (SE) 27.7 (0.8) kg/m2	Very low calorie diet (VLCD) of 600 kcal/day for 2 weeks during run-in period and for 8 weeks during study period followed by a gradual increase in calories during 4-week transition period (800 kcal/day on week 9, 1000 kcal/day on week 10, 1200 kcal/day on week 11, 1500 kcal/day on week 12)	NA	Hyperglycemia not diagnostic of DM (FPG level <126 mg/dL and HbA1c <6.5%) in the absence of active pharmacologic therapy for DM lowering medication(s)	Remission 8 weeks 79% (15/19 subjects) Intention to treat analysis Remission rate of 75% at both 8 and 12 weeks Weight loss Mean (SEM) Over 14 weeks 9.5 (1.8) kg	This small cohort study used a VLCD (total 600 kcal/day) in subjects with T2D <10 years, followed by a gradual return to a 1500 kcal/day diet. Partial remission was achieved by 75% of subjects. Rates of complete remission were not reported but must have been achieved by a sizeable proportion. This study illustrates that more intensive dosing achieves greater remission.

Abbreviations: BMI, body mass index; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; NA, not applicable; T2D, type 2 diabetes; FPG, fasting plasma glucose.