A Scoping Review of Trials Designed to Achieve Remission of Type 2 Diabetes with Lifestyle Intervention Alone: Implications for Sub-Saharan Africa

Figures & data

Figure 1 Flowchart on trial inclusion. *Multiple publications from the same study.

Table 1 Studies Designed to Induce Remission in Newly Diagnosed Treatment Naïve Diabetes (Ordered by Least to Most Restrictive Diet)

Reference and Country	Enrolment Criteria	Number of Participants Race/Ethnicity Gender	Remission Definition	Study Duration and Diet	Counseling and Exercise Program	End of Study Wgt Loss and Metabolic Effects	Remission Rate and Predictors of Remission	Non-Glycemic Effects of LSI
Part A: Dietary and/or Lifestyle Intervention without Specific Caloric Thresholds
O’Dea K. et al 1984 Reference:^Citation23 Australia	Aboriginal People with T2D	N=10 Race/Ethnicity:Aboriginal persons Male: 50% Comparison Group: N=4 Aboriginal persons no T2D	Glucose Criteria for OGTT-1979 ADA Guidelines	7 Weeks Diet Phases: One Diet Diet ad lib in rural area with hunter-gather lifestyle (intake ~1200 kcal/d)	Counseling Traditional lifestyle by moving to and living in rural area Exercise Hunter Gatherer Lifestyle	Weight Loss ↓8±1 kg ~10% of baseline weight Metabolic Effects ↓ Fasting insulin ↑β-cell function	70% (7/10)	Positive ↓TG Negative ↓HDL
Eriksson et al 1991 Reference:^Citation20 Sweden	Enrolled in Malmo Feasibility Study Gender: Male Age:47–49y No T2D symptoms	N=41 Race/Ethnicity White: 100% Male: 100% Other groups: 1)PreD + intervention (n=181) 2)PreD -intervention (n=79) 3)NGT (n=114)	Glucose Criteria for OGTT-1979 ADA Guidelines	6 years Diet Phases: One Diet Dietary advice with no specific calorie restriction	Counseling Group sessions every 6 to 12 months Exercise Subset received 6 months supervised physical training. Regimen not described.	Weight loss ↓Wgt: 2.0–3.3kg ↓BMI: 4% Est wgt loss ~3% Metabolic Effects↓2h insulin	54% (21/39)	Positive ↓Chol ↓BP ↑Physical Fitness ↔TG no change
Dambha-Miller et al 2020 Reference:^Citation19 United Kingdom	Enrolled in ADDITION Cambridge Trial Age: 40–69y	N=867 Race/Ethnicity: White: 97% Male: 61%	A1C<6.5%	5 years Diet Individual counseling with no specific calorie restriction	Counseling 30 min annual review and three 10 min sessions throughout the year. Exercise Not specified	Weight loss ↓ Wgt: ~7%	Remission Rate 30% (257/867) Weight loss (>10%) achieved w/o intensive intervention & and had high likelihood of remission
Roncero-Ramos et al 2021 Reference:^Citation24 Spain	Enrolled in CORDIOPREV Trial (nested study for participants T2D)	N=183 Race/EthnicityNot specified Male: 84%	For 2 years: A1C<6.5% & FPG<126 mg/dL & 2h glucose	5 years Diet Participants randomized: 50%: Mediterranean diet 50%: low fat diet Calories not restricted Both diets, Cholesterol <300 mg/day	Counseling Individual meeting with nutritionists at baseline and q6 months Quarterly group education (20 participants) Exercise Not specified	Weight loss No significant wgt loss	Remission Rate 40% (73/183) Both diets effective in achieved remission without weight loss. Remission highest if baseline hepatic IR low & β-cell fcn high.
Part B: Dietary and/or Lifestyle Intervention with Caloric Thresholds
Ades et al 2015 Reference:^Citation38 United States	A1C: 6.5–8.0% BMI: 27–40 kg/m^2	N=12 Race/EthnicityNot specified Male: 34%	A1C<6.5%	6 months Diet: 500 kcal less than predicted maintenance.	Counseling 24 Weekly group counseling by Registered Dietician Exercise ~2 days/wk 45 min sessions of on-site exercise. ~5 days/wk home walking	Weight Loss ↓10±5 kg (9% of baseline weight) Metabolic Effects: ↓Fasting insulin ↓IR ↓Fat mass ↓WC	Remission Rate 80% (8/10)	Positive ↓TG ↔Chol ↔HDL ↓Chol/HDL Ratio ↓Diastolic BP ↓hsCRP ↑Aerobic capacity
Esposito et al 2014 Reference:^Citation21 Italy	Age: 30–75y BMI>25kg/m^2 A1C: <11%	N=215 Race/EthnicityNot specified Male: 50%	FPG<126 mg/dL and A1C<6.5%	8 years Diet Men: 1800 kcal/d Women: 1500 Kcal/d 50% Low Carbohydrate Mediterranean Diet (LCMD) (N=108) and 50% Low-fat diet (LFD) (N=107)	Counseling Monthly meeting with dieticians in year 1, then bimonthly up to year 4 and every 6 mon thereafter Exercise 175 min of moderate-intensity exercise/wk	Weight Loss Weight loss greater in LCMD than LFD but at end of study mean difference in weight between the two groups was 0.4 kg.	Remission Rate (0%) By 6y, 100% of LFD participants needed OHA. By 8y, 100% of LCMD needed OHA Diet content not wgt loss led to longer remission in LCMD vs LFD.	Positive ↓TG ↓Chol ↑HDL on LCMD ↓HDL on LFT ↓LDL ↓BP
Harayama et al 2013 Referemce:^Citation22 Japan	A1C>6.9% and HOMA-IR≥1.6 BMI: Obese	N=180 Race/EthnicityJapanese Male: 40%	Glucose Criteria for OGTT:1999 ADA Guidelines	6 months Diet Men: 1500 kcal/d “diabetic diet” Women: 1200 kcal/d “diabetic diet”	Counseling Monthly meeting with physician and dietician Exercise 5000 steps/d achieved by walking 30 min after meals.	Weight Loss ↓~13 kg (~14% of baseline wgt) Metabolic Effects ↓fasting insulin ↓IR ↑β-cell function ↓VAT ↓SAT	Remission Rate: 51% (92/180)	Positive Diabetic nephropathy improved

Abbreviations: FPG, Fasting Plasma Glucose; IR, Insulin resistance; OHA, oral hypoglycemic agents; LFT, Liver function tests; ↑↓↔, Post trial change, specifically: increase, decrease or no change, respectively.

Table 2 Studies Designed to Induce Remission in Previously Diagnosed Diabetes After Medications Discontinued (Ordered by Year of Publication)

Reference and Country	Enrolment Criteria	Number of Participants Race/Ethnicity Gender	Remission Definition	Study Duration and Diet	Counseling and Exercise Program	End of Study Weight Loss and Metabolic Effects	Remission Rate and Predictors of Remission	Non-Glycemic Effects of LSI
Henry et al 1986 Reference:^Citation27 United States	Men: BMI≥25 kg/m^2 Women: BMI≥27 kg/m^2 Not treated with insulin	N=10 Comparison Grp: N=5 no T2D Race/EthnicityNot specified Male: 20%	Glucose Criteria for OGTT-1979 ADA Guidelines	5 weeks Diet: 1 Phase TDR:300 kcal liquid diet/d (modified Cambridge Diet)	Inpatient study	Weight Loss ↓11.1±0.7 kg (range 8.1–14.9 kg) ≥9% baseline weight Metabolic Effects ↓Fasting insulin	100% (10/10) had FPG<100 mg/dL.	Positive ↓TG ↓Chol ↔HDL
Lim et al 2011 Reference:^Citation28 United Kingdom	Age: 35–65y BMI: 25–45 kg/m^2 A1C: 6.5–9.0% T2D duration<4y Cr<1.7 mg/dL LFT<2.5 times normal Not treated with insulin.	N=11 Comparison Grp: N=9 Race/Ethnicitynot specified Male: 82%	Remission not defined-Goal was to see if dietary restriction alone ↑ β-cell function and ↓ IR	5 months Diet: 2 Phases Phase 1 (2 months): TDR:600 kcal liquid diet (Optifast) Phase 2 (3 month): Normal eating with dietary advice	Phase 1 Regular phone support, no notation of frequency. Phase 2 Information provided at beginning of phase about healthy eating Exercise Maintain habitual level of physical activity.	Weight Loss ↓15.3± 1.2 kg ≥15% of baseline weight Metabolic Effects After 8 weeks: ↓Hepatic fat ↓Hepatic IR ↓LFT ↑Acute Insulin Response ↓Pancreatic Fat ↓WC	Remission rate not part of study design but at 8 weeks: ↓FPG <106±7 mg/dL ↓<A1C 5.7±0.1%	Positive ↓TG ↔Chol ↔HDL
Steven et al 2016 Reference:^Citation31 United Kingdom	Age 25–80y BMI: 27–45 kg/m^2 A1C<9.5% T2D duration <4y or >8y Cr<1.7 mg/dL	N=30 Race/Ethnicitynot specified Gender not specified	FPG<126 mg/dL	8.5 months Diet: 3 Phases Phase 1 (2 months): TDR:700 kcal liquid diet (Optifast) Phase 2 (2 weeks): food reintroduction Phase 3 (6 months): Wgt maintenance	Phases 1 & 2 Weekly support by phone, text, email and in person visits Phase 3 Individualized plan with monthly reviews Exercise PA encouraged but food behavior prioritized	Weight Loss ↓ ~13 kg ~13% of baseline wgt Metabolic Effects Remitters only: return of first phase insulin response ↓liver TG ↓hepatic IR ↓LFT ↓Fasting Insulin ↓pancreatic TG ↓Fat Mass ↓VAT ↓SAT	43% (13/30) Baseline characteristics of remitters: Younger Age Shorter T2D duration Fewer OHA Higher fasting insulin Lower A1C Lower FPG	Positive ↓TG ↑HDL ↓NonHDL chol ↓BP
Bhatt et al 2017 Reference:^Citation25 India	Persons with T2D enrolled in a low calorie diet program Age: 31–48y BMI: 27–37 kg /m2	N=12 Race/Ethnicity South Asian Male: 67%	A1C<6.5%	3 months One Phase TDR:1000 Kcal/d using 3 liquid servings, plus one “regular” meal & 2 to 3 pre-specified homemade snacks.	Phase 1 Weekly phone & emails Exercise Moderate PA advised	Weight Loss ↓~6.5 kg (~8% of baseline wgt) Metabolic Effects ↓Fasting Insulin ↓IR ↓Hepatic fat ↓LFT ↓WC	50% (6/12) Baseline characteristics of remitters: Younge Age, Shorter T2D duration Fewer OHA Lower A1C Less IR Better β-cell function Higher BMI Higher WC	Positive ↓TG ↔HDL ↔Chol ↔LDL
Romano et al 2019 Reference:^Citation30 Italy	Age: 25–75y BMI: 18–45 kg/m2 T2D<8y Cr<1.7 mg/dL	N=20 Race/Ethnicitynot specified Male: 50%	Goal: determine change in T2D parameters with diet. Remission Criteria not specified	2 months One Phase TDR: Ketogenic diet Men: 650–800 kcal Women: 450 to 600 kcal	Phase 1 Weekly phone contact. Exercise Maintain daily physical activity	Weight loss ↓~15 kg ~15% of baseline wgt Metabolic Effects ↓Abdominal fat mass with preservation of lean mass ↓Fasting Insulin ↓IR ↓LFT ↓WC	Remission rate not stated but mean FPG ↓ from 170±11 to 100±9 mg/dL & A1C ↓from 7.3±0.4% 6.2±0.1%	Positive ↑Renal Function ↓Resting Energy Expenditure
Bynoe et al 2020 Reference:^Citation26 Barbados	Age 20 to 69y BMI≥27 kg/m^2 A1C<12% T2D<6y Cr<1.7 mg/dL LFT ↑ Not on insulin therapy	N=25 Race/EthnicityBlack: 88% Male: 40%	FPG<126 mg/dL	8 months 3 Phases Phase 1 (2 months) TDR: VLCD of 760 kcal/d Phase 2 (1 month) Food reintroduction Phase 3 (5 months): Healthy eating encouraged.	Phase 1 Weekly visits Phases 2 & 3 Monthly visits Exercise “Regular exercise” recommended	Weight loss ↓ ≥10 kg in remitters ≥10% of baseline wgt compared to <10 kg in nonremittters) Metabolic Effects ↑β-cell function ↓WC	60% (15/25) Remitters had higher BMI and WC than non-remitters At baseline and 8 months, individuals who achieved remission had better β-cell function	Positive ↓Diastolic BP ↔TG Negative ↓HDL
Taheri et al 2020 Reference:^Citation32 Qatar	Age: 18 to 50y BMI≥27 kg/m^2 T2D<3y eGFR>45 mL/min No cirrhosis No heart failure	N=70 individuals with T2D and LSI Control Group N=77 individuals with T2D & usual care Race/Ethnicity Middle Eastern & North African Male: 73%	A1C<6.5% and no DM meds for 3 months	1 year 3 Phases Phase 1 (3 months) TDR:~810 kcal/d (Cambridge Weight Plan) Phase 2 (3 months) Food Re-introduction Phase 3 (6 months) Diet managed by participants	Phases 1 & 2 biweekly visits with dietician and trainers Phase 3: Attended clinic once a month Exercise Phases 1 and 2: 10,000 steps/d Phase 3: Unsupervised 150 min/wk	Weight loss ↓12 kg in LSI group ↓4 kg control group Wgt loss of 15% of baseline wgt occurred 21% of LSI group vs 1% of controls Metabolic Effects ↓Fat mass ↓WC	Remission in 61% of LSI vs 12% of controls	Positive ↓BP ↑HDL Negative ↑Chol ↑LDL ↔TG
Thom et al 2021 Reference:^Citation33 United Kingdom	Age: 20–65y BMI:27–45 kg/m^2 A1C<12% T2D <6y Not on insulin therapy GFR>30 mL/min	N=149 Race/Ethnicity White 98% Male: 56%,	A1C<6.5% with no OHA for ≥2 months	2 years 3 Phases Phase 1 (~4 months) TDR:850 kcal/d (shake/soups) Phase 2: (~2 months) Food Re- introduction Phase 3: (18 months) Wgt maintenance	Phase 1 Bi-weekly visits Phases 2 & 3 Monthly visits Exercise No regimen specified	Weight loss Men: ↓ 9±6 kg (~9% of baseline wgt) Women: ↓ 6±6 kg (~6% of baseline wgt) Metabolic Effects ↓Fasting insulin ↑β-cell function	36% (53/149) Remission likely if wgt loss early & >10 kg or 10% baseline wgt Baseline characteristics of remitters: Older age & Male Higher BP Lower A1C Fewer OHA, Lower TG & LFT Less depression Better life quality	Positive ↓TG ↑HDL ↓Systolic BP ↑Quality of life
Quimby et al 2021 Reference:^Citation29 Barbados	Age:20–69 y BMI≥27 kg/m^2, T2D<6y A1C<12%	N=11 Race/Ethnicity Black 100% Male: 10% N=20 individuals with preDM also enrolled.	A1C<6.5% and/or FPG<126 mg/dL	3 months One Phase TDR: 840 kcal/d (4 bottles of Glucerna).	Weekly monitoring at faith-based organization by community health advocate Exercise: No regimen specified	Weight loss ↓6 kg ~6% of baseline wgt	Based on A1C criteria, remission was 60% (6/10). Based on FPG remission was 90% (9/10).	Positive ↓BP

Abbreviations: FPG, fasting plasma glucose; IR, insulin resistance; OHA, oral hypoglycemic agents; LFT, liver function tests; ↑↓↔, post trial change, specifically: increase, decrease or no change, respectively.

Figure 2 Duration and participant number in LSI-alone remission trials. White bars: trials in newly-diagnosed trials; black bars: trials in established T2D.

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