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. 2023 Mar 9;14:1118848. doi: 10.3389/fendo.2023.1118848

Table 1.

Summary of clinical trials on T2DM prevention with glucose lowering drugs and weight-loss medications.

Study (year) Eligibility Number of Subjects Interventions Results Mean or Median Follow up in years Comments
A) Metformin
DPP (1996–2001) (6) IFG and IGT 3234 study participants
531 subjects with IGT
LSM vs. Metformin 850mg BD vs. placebo LSM group reduced their risk of developing T2DM by 58% and metformin by 31% 2.8 10-year follow-up ( 7): T2DM incidence was reduced by 34% (24–42) in the lifestyle group and 18% (7–28) in the metformin group compared with placebo.
15 years follow-up ( 8): T2DM incidence was reduced by 27% in the lifestyle intervention group (HR 0.73, 95% CI 0.65-0.83; p<0.0001) and by 18% in the metformin group (0.82, 0.72-0.93; p=0. 001), compared with placebo
22-year follow-up (9):
Relative risk reduction in T2DM by 25% in the lifestyle intervention and by 18% in the metformin group.
IDPP (2006) (10) IGT 531 LSM vs. Metformin vs. LSM + metformin vs. placebo Risk reduction for T2DM with LSM was 28.5%, metformin 26.4%, and combination 28.2% compared to placebo 30 months
CDPP (2001) (11) IGT 321 LSM vs. Acarbose 50 mg TID vs. metformin 250 mg TID vs. placebo Annual incidence of T2DM was 11.6% for the control, 8.2% for LSM, 2% for acarbose, and 4.1% for metformin. 3.0
EDIT (2003) (12) IGT and IFG 631 Acarbose 50 mg TID vs. metformin 500 mg TID vs. placebo 8% risk reduction with acarbose and 37% with metformin, compared to placebo 6.0 6-year follow-up (13):
No differences in relative risk for diabetes with acarbose (1.04, P = 0.81), Metformin (0.99, P = 0.94) or combination therapy (1.02, P = 0.91). In those with IGT at baseline, relative risk was reduced significantly with acarbose (0.66, P = 0.046) but not Metformin (1.09, P = 0.70) or combination therapy (0.72, P = 0.27).
Begum MR et al. (2009) (14) Nondiabetic –PCOS. Pregnant 29 patients on metformin during pregnancy compared with 30 controls. Metformin 2 – 2.5 g per day vs. controls GDM developed in 3.44% of patients on metformin compared to 30% in controls Gestation period PCOS use of metformin throughout pregnancy is associated with and might be responsible for a ninefold reduction (30-3.44%) of GDM
Glueck et al. (2002) (15) Nondiabetic –PCOS. Pregnant 33 patients on metformin compared with 39 controls Metformin 850 mg TID vs. controls In PCOS use of metformin is associated with a 10-fold reduction in GDM (31 to 3%) Gestation period
Tao Tao et al. (2021) (16) PCOS + prediabetes (IFG and/or IGT) 150 women with PCOS Exenatide (10-20μg daily), Metformin (1500-2000 mg daily), or Combination (Exenatide plus Metformin) Remission rate of prediabetes: Combination group (64%, 32/50) and exenatide group (56%, 28/50) was significantly higher than that of the metformin group (32%, 16/50) (P = .003 and.027, respectively) 12 weeks
Guardado-Mendoza et al. (2019) (17) IGT 144 Linagliptin 5 mg + metformin 1700 mg daily + lifestyle (LM group) or metformin 1700 mg daily + lifestyle (M group) T2DM incidence was higher in M group in comparison to LM group (HR 4.0, 95% CI: 1.24-13.04, p = .020). The probability of achieving normoglycemia was higher in LM group (OR 3.26 CI 95% 1.55-6.84). 2.0
Daniele G et al. (2020) (18) History of GDM + IGT or IFG 40 Sitagliptin (100 mg qd), Metformin (850 mg bid) or both (50 + 850 mg bid) for 16 weeks Among Metformin + sitagliptin women, 33% reverted to normal glucose tolerance (NGT) compared with 14% with Metformin alone and 7% with Sitagliptin (P < 0.05) 16 weeks
B) Thiazolidinediones
TRIPOD (2002) (19) Hispanic women with previous GDM 266 Troglitazone 400 mg/day vs. placebo 55% reduction in the incidence of T2DM in troglitazone arm 2.5
PIPOD (2006) (20) Hispanic women with previous GDM Open label study on 89 women without T2DM in TRIPOD A Pioglitazone 45 mg/day Annual T2DM incidence was 4.6%
ACT NOW
(2011) (21)
IGT
Mean BMI 33.4 kg/m2
602 Pioglitazone 45 mg/day vs. placebo Annual incidence rates for T2DM mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to T2DM in the pioglitazone group was 0.28 2.4 Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007)
DREAM (2006) (22, 23) IGT and/or IFG
Mean BMI 30.8 kg/m2
5269 Rosiglitazone 8 mg/day vs. placebo and Ramipril 15 mg/day vs. placebo 3-year T2DM incidence: Ramipril: HR 0.91 (0.80–1.03) Rosiglitazone: HR 0.38 (0.33–0.44)
HF results: 14 (0·5%) participants in the rosiglitazone group and two (0·1%) in the placebo group developed heart failure (p=0·01).
3.0 Balancing both the benefits and risks suggests that for every 1000 people treated with rosiglitazone for 3 years, about 144 cases of T2DM will be prevented, with an excess of four to five cases of congestive heart failure.
C) Alpha-glucosidase inhibitors
CDPP See above
STOP NIDDM (2002) (24) IGT
Mean BMI 31.0 kg/m2
1418 Acarbose 100 mg TID vs. placebo 25% relative risk reduction on acarbose compared to placebo. Absolute risk reduction after 3.3 years was 9.1%. 3.3 Additional studies showed that acarbose was associated with 49% reduction in cardiovascular events (15 vs. 32 subjects; HR 0.51, 95% CI 0.01–0.95, p=0.03). Interpret with caution due to small number of events.
NNT 11 for 3.3 years
Ryuzo Kawamori et al. (2010) (25) IGT 1780 Voglibose 0.2 mg TID vs. placebo Subjects treated with voglibose had a significantly lower risk for the progression to T2DM than placebo (50/897 vs 106/881: hazard ratio 0.595). 4.0 810 (90%) of 897 patients in the voglibose group had adverse events. Serious adverse events (all one each) in the voglibose group were cholecystitis, colonic polyp, rectal neoplasm, inguinal hernia, liver dysfunction, and subarachnoid hemorrhage.
EDIT See above
D) Sodium-glucose co-transporter 2 (SGLT2) inhibitors
Rossing, et al. (2022) (26) No h/o diabetes and HbA1C less than 6.5%.
Mean GFR: 58.7
Mean BMI: 27.4 kg/m2
4003 (1398 [34·9%] from the DAPA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) Dapagliflozin vs placebo 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed T2DM (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). 1.8
Weight-loss medications:
A) Orlistat
XENDOS (2004) (27) Obese and normal (79%) or IGT (21%)
Mean BMI 37.3 kg/m2
3,305 LSM plus either orlistat 120 mg or placebo, three times daily. Diabetes risk reduction of 45% compared to placebo 4.0 Overall, 4% of placebo patients and 8% of orlistat patients withdrew from the study because of adverse events, primarily GI due to gastrointestinal events.
B) Phentermine-Topiramate
CONQUER (2011) (28) Overweight or obese adults and two or more comorbidities (hypertension, dyslipidemia, T2DM or prediabetes, or abdominal obesity)
Mean BMI 36.2 kg/m2 (low dose)
36.6 kg/m2 (high dose)
2487
(1684 (68%) had IGT or IFG)
Placebo vs once-daily phentermine 7·5 mg plus topiramate 46·0 mg vs once-daily phentermine 15·0 mg plus topiramate 92·0 mg. the relative risk (vs placebo) was 0·78 (0·40–1·50) with phentermine 7·5 mg plus topiramate 46·0 mg, and 0·47 (0·25–0·88) with phentermine 15·0 mg plus topiramate 92·0 mg 1.0
C) Lorcaserin
CAMELLIA-TIMI 61 (29) BMI ≥27 kg/m2 with or at high risk for atherosclerotic vascular disease; Age ≥ 40 years Total N: 12,000
At baseline, 6816 patients (56.8%) had T2DM, 3991 (33.3%) prediabetes, and 1193 (9.9%) normoglycemia.
Lorcaserin 10mg BID or placebo Lorcaserin reduced T2DM incidence by 19% (HR, 0.81; 95% CI: 0.66– 0.99) in patients with prediabetes and by 23% in patients without diabetes (HR 0·77, 95% CI: 0·63–0·94). 3.3

DPP, Diabetes Prevention Program; IDPP, Indian Diabetes Prevention Program; CDPP, Chinese Diabetes Prevention Program; EDIT, Early Diabetes Intervention Trial; STOP NIDDM, Study to prevent non-insulin dependent diabetes; TRIPOD, Troglitazone in Prevention of Diabetes; PIPOD, Pioglitazone in Prevention of Diabetes; ACT NOW, Actos Now for the prevention of diabetes; DREAM, Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications; LSM, Lifestyle modifications; IGT, Impaired glucose tolerance; IFG, Impaired fasting glucose; GDM, Gestational diabetes mellitus; BD, Twice daily; TID, Thrice daily; CKD, chronic kidney disease; GFR, Glomerular Filtration Rate; XENDOS: XENical in the prevention of diabetes in obese subjects study, CONQUER: Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults, CAMELLIA-TIMI: Effect of lorcaserin on treatment and prevention of type 2 diabetes in overweight and obese patients.