Table 3.

Type 2 Diabetes Interventions With Subtherapeutic Dosing.

First author, publication year (ref), study design/study duration (months)/study population	Total enrolled/analyzed [F%]; N, baseline mean age (SD), and BMI (SD)	Intervention treatment	Control treatment	Remission definition	Remission rate and weight loss (kg) or change in BMI (kg/m2)	Dosing effectiveness comments
Ades, 2015,28 single-arm intervention study Duration: 6 months Overweight/obese (BMI 35.8 ± 4.3 kg/m2), sedentary, and unfit (peak VO2 20.7 ± 4.7 mL/kg/min) and recently (<1 year) diagnosed with type 2 diabetes Exclusions: Taking hypoglycemic medication	12/10 [83%] 62 (6) years 35.8 (4.3) kg/m2	Behavioral weight loss counseling (24 weekly group counseling sessions coordinated by a RD and focused on self-monitoring and developing an action plan for diet and physical activity), daily caloric goal of 500 kcal less than predicted maintenance calories, supervised exercise (nearly daily sessions of “high-caloric expenditure exercise” with 1-3, 45-60 minute sessions/week of supervised onsite exercise and home walking on other days for a total of 5-6 days per week of exercise [intensity set at 50% to 60% peak VO2])	NA	Complete remission is an HbA1c level <5.7%	Complete remission rate = 10% (1/10 participants) Average weight loss: 9.7 (5.2) kg or 9%	This small study used a subtherapeutic dose of lifestyle interventions with exercise and an energy deficit diet of −500 kcal/day. Though fitness improved significantly, results indicate that exercise did not compensate for the subtherapeutic dietary intervention.
Gow, 2017,25 single-arm intervention Duration: 8 weeks of very-low-energy-diet (VLED) 34 weeks hypocaloric diet Patients divided into adherers (≥5% body weight loss during the 8-week VLED) and non-adherers Australian and New Zealand youth, age <18 years, obese, type 2 diabetes	8/8 [100%] for 8-week VLED 8/5 [63%] for 34 weeks hypocaloric diet Age median (range) 14.4 (7.5-16.8) years Weight mean (SE) 86.2 (10.2) kg	Weeks 0-8 VLED 800 kcal/day <40% carbohydrate 40-55% protein <20% fat Weeks 9-12 Transition to reduced-energy diet, weaning away from meal replacements Weeks 13-24 Hypocaloric diet (45% to 55% moderate glycemic index and minimal refined carbohydrate, 15% to 25% protein and ~30% fat where ≤10% saturated) Support given throughout via regular telephone/text message contact	NA	HbA1c levels <6.5%, fasting plasma glucose <7.0 mmol/L or 2-hour post-glucose load plasma glucose <11.1 mmol/L	Remission All participants 50% Adherers only After 34 weeks = 80% Weight loss All participants Mean (SD) weight loss after 8-week VLED = 4.1 (4.0) kg or 5.0 (4.3) % body weight Adherers Median weight loss after 8-week VLED = 7.5%; median (range) weight loss after 34 weeks = 6.7 (3.4-13.2) kg, or 12 (3.7-14.3) % body weight Non-adherers Median weight loss after 8-week VLED = 0.5%, after 34 weeks NA (all non-adherers discontinued participation)	This small study illustrates the potential of intensive lifestyle changes to produce remission when properly dosed. It also illustrates the ineffectiveness of insufficiently dosing lifestyle changes in the non-adherent subjects.
Gregg, 2012,26 ancillary observational analysis of LookAHEAD randomized controlled trial 48 months US adults, 45-76 years, BMI ≥25 kg/m2, type 2 diabetes Excluded if: • HbA1c>11% • BP >160 mm Hg systolic or >100 mm Hg diastolic • TAG >600 mg/dL • Unable to perform a maximal graded exercise test • Unable to complete 2 weeks of diet and activity self-monitoring	5145/4503 [88%] Intervention N = 2241 58.6 (6.7) years 35.8 (5.9) kg/m2 Control N = 2262 59.1 (6.9) years 35.9 (5.7) kg/m2	“Intensive lifestyle intervention” (ILI) First 6 months: weekly group and individual Second 6 months: 3 sessions per month Years 2-4: 2 sessions per month and regular refresher group series Goals: Reduce total caloric intake to 1200 to 1800 kcal/d through reductions in total and saturated fat intake and by increasing physical activity to 175 min/week Liquid meal replacements provided	Diabetes support and education (DSE) 3 group sessions per year on diet, physical activity, and social support	Full normalization of glucose (fasting plasma glucose level <100 mg/dL and HbA1c <5.7%) with no anti-hyperglycemic medication	2-Year Intervention: 9.2% (95% CI: 7.9% to 10.4%) Control: 1.7% (95% CI: 1.2% to 2.3%; P .001) 3-Year Intervention: 6.4% (95% CI: 5.7% to 7.4%) Control: 1.3% (95% CI: 0.8% to 1.7%; P NR) 4-Year Intervention: 3.5% (95% CI: 2.7% to 4.3%) Control: 0.5% (95% CI: 0.2% to 0.8%; P = .02) Weight loss: ~3.5%	The LookAHEAD study used what they called “intensive lifestyle interventions” (ILI), which consisted of a modest energy restriction (1200-1800 kcal/day) with exercise. The modest weight loss and minimal remission reveals the lifestyle changes were insufficiently dosed. Compare these results to outcomes of studies in the therapeutic table above (DiRECT, Counterpoint, etc. The LookAHEAD trial illustrates why lifestyle change has been considered ineffective—underdosed LM interventions are ineffective.
McInnes, 2017,27 3-arm parallel randomized controlled trial 8 or 16 weeks intervention plus follow-up until 52 weeks (12 months total) Patients of Diabetes Care and Research Program at Hamilton Health Sciences; 30-80 years, T2D for up to 3 years, BMI ≥23 kg/m2	83/83 [100%] 8-Week intervention N = 28 57.1 (10.3) years 34.7 (7.0) kg/m2 16-Week intervention N = 27 55.1 (9.2) years 33.3 (5.5) kg/m2 Control N = 28 58.2 (11.1) years 31.6 (4.4) kg/m2	In-person and phone counseling reduction of daily kcal by 500-750 Treatment with metformin, acarbose, and insulin glargine Moderate physical activity >150 min/day	Standard diabetes care	Complete remission FPG < 6.1 mmol/L and 2-hour plasma glucose < 7.8 mmol/L on an OGTT Or HbA1c <6.0% and no chronic diabetes drugs (% participants)	8-Week group Using OGTT criteria: at 20 weeks post randomization, complete remission = 7.1%; HbA1C criteria: 20 weeks post-randomization, complete remission = 10.7% 16-Week OGTT criteria: 20 weeks post-randomization, complete remission = 14.8%; 28 weeks post-randomization, complete remission = 7.4%; HbA1C criteria: 28 weeks post-randomization, complete remission = 14.8% Control group OGTT criteria: 28 weeks post-randomization, complete remission = 3.6%; HbA1C criteria: at 28 weeks post randomization, complete remission = 7.1% Weight loss 20-week post-randomization weight loss mean % (SD): 8-week: 3.1 (3.4) 16-week: 5.1 (3.3) Control: 1.4 (2.4)	This RCT used a moderately hypocaloric diet (reduced by 500-750 kcal/day) with moderate physical activity (>150 min/day). This moderate dosing achieved moderate complete remission rates of ~7% to ~15%. Exercise levels were not measured, but BMI changes indicate moderate weight loss occurred. This study shows that exercise cannot compensate for an insufficient dietary energy deficit.

Abbreviations: BMI, body mass index; NA, not applicable; BP, blood pressure; CI, confidence interval; T2D, type 2 diabetes; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; RCT, randomized controlled trial.