The Effect of Sodium Glucose Co-transporter 2 Inhibitor (dapagliflozin) on Weight Loss in Non-diabetic Adults with Obesity: Triple-blinded, Randomized, Placebo-controlled Trial.

Background Obesity is a disease, generally defined as a body mass index (BMI) ≥ 30 kg/m2,1 is a global issue that continues to grow at an alarming rate, imposing serious threat to individuals, public health, and the economy. The prevalence of overweight and obesity has tripled since 1975, with 1.6 billion overweight adults and 650 million obese adults, according to World Health Organization report.2 In Oman, non-communicable diseases (NCDs) represent a major burden on healthcare system at which 185.75 deaths per 100,000 population are attributed to NCDs.3 Obesity is an independent risk factor for most NCDs, adding to disease morbidity and mortality. According to a national survey conducted in 2017, the prevalence of obesity and overweight were 30.7% and 66.1%, respectively, with higher prevalence in females compared to males.4 The Look AHEAD trial revealed that losing 5% to 10% of body weight through diet and exercise alone has been associated with reduced risk of cardiovascular disease in obese and overweight adult patients.5 Whilst healthy lifestyle is the mainstay for obesity management, there is a growing interest over pharmaceuticals that support weight loss and prevent metabolic complications.

The US Food and Drug Administration (FDA) approved five drug therapies to treat obesity, namely orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, liraglutide, and recently saxenda,6 while the European Medicines Agency (EMA) supported three drug therapies, orlistat, bupropion/naltrexone and liraglutide.7 Several anti-diabetic drugs have been authorized for weight loss even for patients without diabetes.8 Sodium glucose cotransporter 2 inhibitors (SGLT2i) including empagliflozin, dapagliflozin and canagliflozin are classes of hypoglycemic agents that have been studied in both human and animal models to measure their glycemic and metabolic effect. These drugs reduce plasma glucose levels by inhibiting the sodium glucose cotransporter 2, located in the proximal tubule of the kidney, leading to increased urinary glucose excretion and a reduction in plasma glucose levels in patients with type 2 diabetes mellitus (T2DM).8-11 This mechanism of action was found to lower the risk of hypoglycemia, with additional benefits of weight loss, reductions in blood pressure, cardiovascular (CVD), and chronic kidney disease risk (CKD). 8, 12, 13 The drugs are prominent in most recent guidelines for the management on T2DM and are particularly recommended when, in addition to glucose lowering, there is a compelling need to reduce body weight.14 Weight reduction via behavior change and maintaining healthy lifestyle is the first line and cost-effective treatment for obesity. According to the US Preventive Services Task Force, all adults aged 18 years or above should be screened for obesity and intensive behavior intervention to be given for weight loss,15 with at least one session per month for at least three months.16 Body mass index (BMI) is a key indicator for weight assessment; however waist circumference may be an acceptable alternative in people with central obesity because BMI may not account for the cardiovascular risk of central adiposity.17

Dapagliflozin is a highly selective SGLT2i that blocks the reabsorption of 80% - 90% of the glucose filtered by the glomerulus. It is an oral medication with three different dose strengths; 2.5 mg, 5mg, 10 mg once daily, in addition to the combination formula with metformin; dapagliflozin/ metformin, with strength of 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg, 10mg/500mg, and 10mg/1000mg. Several RCTs have shown its effectiveness on glycaemic control, weight loss, and blood pressure in patients with T2DM, in addition to the cardiovascular and renal protection.24 A randomized placebo control trial (RCT) that enrolled 534 patients with T2DM on preceding metformin treatment investigated the effectiveness of dapagliflozin 2·5 mg, 5 mg, and 10 mg per day dose versus placebo, over 24 weeks. There was a dose dependent reduction in HbA1c in patients treated with dapagliflozin, with a reduction of 0·84% in patients assigned to a maximum dose of 10 mg per day compared with a reduction of 0·3% in the placebo group, at the end of study period. Mean HbA1c had decreased by -0·30% (95% CI -0·44 to -0·16) in the placebo group, compared with -0·67% (-0·81 to -0·53, p=0·0002) in the dapagliflozin 2·5 mg group, -0·70% (-0·85 to -0·56, p<0·0001) in the dapagliflozin 5 mg group, and -0·84% (-0·98 to -0·70, p<0·0001) in the dapagliflozin 10 mg group.25 The trial also showed no apparent changes in fasting lipid profiles, apart from greater mean increases in HDL cholesterol (1·8-4·4% vs 0·4%) and decreases in triglycerides (-2·4% to -6·2% vs 2·1%) compared with placebo.25 Treatment with dapagliflozin was not superior to placebo in reducing the risk of major adverse cardiovascular events but lowered the risk of hospitalization due to heart failure or death from CVD (hazard ratio: 0.83; 95% CI, 0.73 to 0.95; P=0.005).26 In patients with established chronic renal disease with an estimated glomerular filtration rate (eGFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and/ or urinary albumin-to-creatinine ratio of 200 to 5000) who received dapagliflozin 10 mg a day, showed a significantly lower risk for sustained decline in the estimated eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes than with placebo. The hazard ratio for renal dysfunction or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001) in dapagliflozin compared with placebo and a hazard ratio 0.71 (95% CI, 0.55 to 0.92; P=0.009) for death from cardiovascular causes or hospitalization for heart failure.27 In patients with mild to moderate chronic kidney disease of diabetes, no alterations in mean renal function measures, including serum creatinine concentration, were reported.28 The most common side effects of dapagliflozin were urinary and genital infection, 29 besides headache, backpain, and diarrhea.30 An analysis of published data from 12 RCTs, included 3152 patients who received dapagliflozin 2.5 mg, 5 mg, or 10 mg as monotherapy or add-on treatment, and 1393 placebo-treated patients, showed that the diagnosis of infection were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. However, most infections were treated and responded to antimicrobial therapy. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient.30 Most studies were in patients with diabetes who are at risk of asymptomatic bacteriuria and pyelonephritis in combination with dysfunction of the urinary tract compared with people without diabetes, the fact that further studies with longer observation period are required to confirm that infection is related to the drug and not diabetes status.31 In fact, it has been found that the frequency of serious adverse effects including urinary and genital fungal infection from dapagliflozin were comparable to placebo in patients with T2DM.30 Dapagliflozin and obesity management Obesity and T2DM are intrinsically linked with multiple shared pathology, besides being associated with increased risk of multiple comorbidities.32 The weight loss observed with SGLT2i is thought to be due to fluid loss, reduction in lean body mass, and thereafter loss of calories via increased urinary glucose excretion. Dapagliflozin was found to improve adipocyte function by lowering inflammatory markers, C-reactive protein and increasing adiponectin besides lowering glycated hemoglobin and body weight, however evidence was inconclusive due to small sample size.33 Animal based trials are still ongoing to provide evidence of actual mechanism of weight loss with SGLT2i. Modest body of evidence have shown the effectiveness of dapagliflozin in causing clinically significant reductions in body weight.34 A double-blind placebo-controlled study of 182 patients with T2DM treated with dapagliflozin 10mg a day versus placebo (added on metformin) over 102 weeks showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increases in rate of hypoglycemia, in former drug compared with later placebo. In addition to that, no significant changes from baseline in bone density or markers of bone turnover, compared with placebo. The frequency of patients with at least one adverse event (mainly urinary and genital infections) were comparable; 71.4% in the dapagliflozin and 69.2% in placebo group by week 102. 35 Another RCT compared the metabolic effect of dapagliflozin versus placebo on high density lipoprotein (HDL-C) over 16 weeks of treatment, showed reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass, without evidence of improving HDL-cholesterol.36 Treatment with dapagliflozin 5 mg/day over 24 weeks showed a decrease in total body weight of 2.9kg (3.9%). Furthermore, there was a decrease in serum alanine aminotransferase and γ-glutamyl transpeptidase levels and a significant decrease in controlled attenuation parameter (CAP)- a measure of liver stiffness and fibrosis from 314 ± 61 to 290 ± 73 decibel dibutyryl (dB)/m (P = 0.0424), concluding that dapagliflozin might improve liver steatosis in patients with type 2 diabetes and NAFLD. However, the possibility that a reduction in body weight or visceral adipose tissue by dapagliflozin may be associated with a decrease of liver steatosis or fibrosis, cannot be excluded.37 A small, prospective study of 26 patients with T2DM who received dapagliflozin 5mg/day over 12 weeks showed a 23.8% loss of lean body mass but modest weight loss of 2.5 Kg.36 A randomized double blind placebo control trial showed that empagliflozin monotherapy at doses of 10 mg and 25 mg for ≥76 weeks was well tolerated and led to sustained reductions in glycated hemoglobin (HbA1c) and weight compared with placebo.37 The glucose-dependent mechanisms of action of SGLT2-i comes with low risk of hypoglycemia, particularly when not used with sulphonylureas or insulin.38 Several studies have been undertaken to evaluate and measure the effectiveness of SGLT-2i in managing obesity in diabetic and non-diabetic patients, however evidence is inconclusive and necessitates further high-quality trials to assess the long-term outcomes of this drug that is administered orally, once daily dose, with expected low risk of severe adverse events.

The trial will evaluate the efficacy and safety of dapagliflozin compared to metformin and placebo in weight loss management in young adults with obesity, who are not yet diagnosed with diabetes.

Methods: