Table 2.

SGLT2 inhibitor trials looking at the efficacy of SGLT2 inhibitors on metabolic outcome in patients without diabetes.

Author, year, country	N, Median age, Female (%), DM (%)	Type of study	Selection criteria	Treatment group	Comparison group	Median follow-up	Primary outcome	Secondary outcome	Effect size	Study conclusion
Bays et al., 2013, US [56]	376, 44.8, 88 %, DM (0 %)	Intent to treatRandomized double blind placebo- controlled trial	Adult aged 18–65 years with BMI between $\ge$ 30 and < 50 kg/m2 or with wither lower BMI in presence of hypertension	Canagliflozin (50 mg,100mgor300mgoncedaily)	Placebo	12 weeks	% change in body weight from baseline to week 12	Absolute change in body weight% change in body weightChange in BMI	Canagliflozin increase urinary glucose excretion in a dose dependent manner and results in statistically reduction in body weight compared to placebo.Least square mean percent changes from baseline of −2.2 %, −2.9 %, 2.7 % and 1.3 % at doses of 50, 100, 300 mg and placebo (p < 0.05)	In overweight and obese subjects without diabetes, Canagliflozin significantly reduce body weight compared to placebo
Hollander et al., 2017, ermany [57]	334, 45.7, 81.7 %, DM (0 %)	Randomized control double-blind parallel group placebo-controlled multicenter parallel-group trial	Overweight and obese adults aged 18–65 years without type 2 diabetes who had BMI $\ge$ 30 and < 50 kg/m2 or had BMI $\ge$ 27 and < 50 with comorbidities like HTN and/or dyslipidemia without diabetes	Canagliflozin (300 mg/day) Or Phentermine OrCanagliflozin + Phentermine	Placebo	26 weeks	% change in body weight from baseline to week 26	Proportion of individual achieving weight loss $\ge$ 5 % and change from baseline in SBP	Statistically superior weight loss from baseline for Canagliflozin/Phentermine compared to placebo at 26 weeks (mean difference −6.9 % with p < 0.001Statistically significant achievement of weight loss $\ge$ 5 % and reduction of SBP for Canagliflozin/Phentermine	Canagliflozin/Phentermine produced meaningful reduction in bodyweight and well tolerated in overweight/obese individuals with type II diabetes
Lundkvist et al., 2016, Sweden [58]	50, 52, 61 %, DM (0 %)	Double blinded randomized controlled trial	Obese man and woman aged 15–70 years without diabetes, hypertension, and BMI of 30–45 kg/m2	Dapagliflozin (10 mg/day) + subcutaneous long acting exenatide 2 mg once daily	Placebo	24 weeks	Change in body weight from baseline to 24 weeks	Percent change in body weight from baseline. Efficacy on SBP, waist hip ratio, glycemic measures	The difference of body weight change was −4.13 kg (p < 0.001) attributable to adipose tissue reduction 36 % vs 4.2 % of participants achieved $\ge$ 5 % body weight loss	Dual treatment with Dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeksWell tolerated with minimal side effects
Gonzalez-Ortiz et al., 2017, exico [59]	26, 45, 84.6 %, DM (0 %)	Randomized double-blinded, placebo-controlled clinical trial	Overweight subjects with BMI of 25–29.9 kg/m2 without hypertension	Dapagliflozin (10 mg/day)	Placebo	12 weeks	Change in body weight at 12 weeks	Renal composite outcomeDeath from any causeHospitalization for HF	Significant improvement of weight, BMI, fat mass, SBP, visceral adiposity.No significant effect on DBP, glucose changes	Dapagliflozin has significant effect on reduction in body weight, visceral adiposity, BMI and SBP in overweight subjects
Neeland et al., 2020, US [60]	35, 53, 62.9 %, DM (0 %)	Randomized double blind placebo-controlled trial	Age $\ge$ 18 years, obese, BMI $\ge$ 30, nondiabetic, able to undergo neck to knee MRI scan for body fat assessment	Empagliflozin (10 mg/day)	Placebo	3 months	Change in body weightDecrease in HbA1cGlycerol derived gluconeogenesis	Fasting blood glucose, serum insulin level, TG, plasma free glycerol, adiponectin, alanine aminotransferase, norepinephrine	6.5 % increase (p = 0.005) increase in area under curve for glycerol-derived 13C enrichment in treatment group	Empagliflozin reduced endogenous glycerol-gluconeogenesis in obese adults without diabetes. SGLT2 inhibitors may prevent type 2 diabetes in obesity
Ramirez-Rodriguez et al., 2020, Mexico [50]	24, 46.7, 70.83 %, DM (0 %)	Randomized double blinded placebo-controlled clinical trial	Subjects with prediabetes	Dapagliflozin (10 mg/day)	Placebo	3 months	Change in body weight, BMI, waist circumference, fasting glucose	Change in uric acid level	Significant decrease in body weight (p = 0.01), BMI (p = 0.023), waist circumference (p = 0.003), fasting blood sugar (p < 0.001) and uric acid (p = 0.03)	Dapagliflozin in patients with prediabetes significantly decreased body weight, BMI, waist circumference, fasting blood sugar, uric acid and increase insulin sensitivity
Ryan et al., 020, US [51]	50, 35, 76 %, DM (0 %)	Randomized double blinded placebo-controlled clinical trial	Adults of age 18–65 years with BMI > 27.5 kg/m2 sedentary, with no known metabolic disease	Dapagliflozin (5 mg/day) for first 14 days and then increased to Dapagliflozin (10 mg/day) for rest of the study period	Placebo	12 weeks	Fat free massRise in HDL cholesterol	Dietary preference, hunger, appetite	Dapagliflozin combined with dietary counselling resulted in significant reduction in fat free mass (p = 0.04) and attenuated the rise in HDL cholesterol (p = 0.028)	Careful consideration of decrease in fat free mass is indicatedLonger duration of SGLT2 inhibitors evoked measurable effects on dietary preference, hunger and appetite
Elkind- Hirsch et al., 2021, US [52]	92, 28, 100 %, DM (0 %)	Randomized single blind trial	Subjects with BMI of 30–45 kg/m2 and PCOS	Exenatide (EQW) (2mgweekly)Dapagliflozin (DAPA (10 mg/day)Exenatide plus DapagliflozinDapagliflozin plus metforminPhentermine topiramate (PHEN/TPM)	–	24 weeks	OGTTFasting insulinWeightBlood pressureWaist circumferenceBody composition	Not reported	Significant difference among the five different treatment groups for mean blood glucose (p < 0.02), BMI (p < 0.005), waist circumference (p < 0.035), fasting blood glucose (p < 0.0001) and OGTT (p < 0.0001)Dual treatment with EQW/DAPA was superior to either DAPA alone, DAPA/metformin and PHEN/TPM	Dual treatment with EQW/DAPA was superior to either DAPA alone, DAPA/metformin and PHEN/TPM in terms of clinical and metabolic benefits
Faerch et al., 2020, Denmark [53]	112, 57.2, 55.83 %, DM (0 %)	PRE-D trial—Randomized controlled parallel multicenter open-label non blinded study	Overweight subjects with BMI $\ge$ 25 kg/m2 and prediabetes	Dapagliflozin (10 mg/day)Metformin (1700mgdaily)Interval-based exercise	Placebo	26 weeks	Change in the mean amplitude of glycemic excursions (MAGE), measure of glycemic variability between baseline and 13 weeks	Change from baseline to mid-point of treatment, end of treatment and follow up for MAGE, fasting plasma glucose, fasting serum insulin, body weight, waist hip ratio, blood lipids, OGTT	Compared to control group, there was a small difference in MAGE in Dapagliflozin group (p = 0.04) and a small non-significant reduction in exercise group (p = 0.067) and unchanged in Metformin.	Treatment with Dapagliflozin and interval-based exercise lead to similar but small improvements in glycemic variability compared to control and metformin therapy
Kullmann et al., 2022, Germany [54]	40, 62.5, 60 %, DM (0 %)	Double-blind, randomized placebo-controlled trial	Adult aged 30–75 years with BMI $\ge$ 25 and < 40 kg/m2 and impaired fasting glucose	Empagliflozin (25 mg/day)	Placebo	8 weeks	Insulin responsiveness of brain	Fasting plasma glucose, total adipose tissue content, liver fat content	Empagliflozin increased hypothalamic insulin responsivity and decrease in fasting blood glucose and liver fat	Empagliflozin may reverse brain insulin resistance with potential benefits for adiposity
Veelen et al., 2022, Netherlands [55]	14, 42.85, 66.3 %, DM (0 %)	Randomized double blind placebo-controlled crossover trial	Adult 40–75 years with BMI 27 to 38 with prediabetes and sedentary lifestyle	Dapagliflozin (10 mg/day)	Placebo	2 weeks	Body weight, HbA1c, SBP, DBP, 24-hour urinary glucose excretion, 24-hour energy expenditure, energy metabolism during daytime and night-time	Hepatic and skeletal muscle glycogen, mitochondrial oxidative metabolism, hepatic lipid content	Compared to placebo, Dapagliflozin had higher 24-hour urinary glucose excretion (p < 0.0001), daytime respiratory exchange ratio (p = 0.046), nighttime respiratory exchange ratio (p = 0.019), higher maximal mitochondrial oxidative capacity (p = 0.007) and lowers SBP (p = 0.025), DBP (p = 0.023).No difference for skeletal muscle glycogen, fasting plasma glucose, free fatty acid, and food preference	Dapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations, skeletal muscle metabolism, improved fat oxidation and mitochondrial oxidative capacity.

BMI – body mass index; SBP – systolic blood pressure; DBP – diastolic blood pressure.