Treatment of Obesity with Drugs SGLT-2 Inhibitors: Benefits and Limitations-A Literature Review

Obesity is one of the most relevant medical problems of the modern world, which requires a comprehensive approach to treatment and prevention. The mainstays of obesity treatment are diet and adequate physical activity, but when these weight loss measures are insufficient, medical drugs and/or metabolic surgery should be added to the treatment regimen. One of the newest trends in the medical treatment of obesity is the use of drugs that remove glucose from the urine, including inhibitors of sodium-dependent glucose cotransporter type 2 (SGLT-2 inhibitor).

Purpose: based on data from literature sources, to investigate the effect of SGLT-2 inhibitor on weight loss in obesity.

Subject: SGLT-2 inhibitor drugs and their effect on body weight in obesity.

Research methods: a review of literary sources.

Results: According to a meta-analysis of randomized clinical trials, SGLT-2 inhibitor drugs reduced body weight with statistical significance in overweight or obese adults without diabetes. Given the limited weight loss and potential harm, SGLT-2 inhibitors should be considered as an alternative treatment for weight loss in addition to lifestyle interventions in these patient groups, in the setting of low risk of sexually transmitted infections and urinary tract infections. For a more in-depth study of this current topic, further studies with large samples and longer periods are needed.

Conclusions: Treatment of obesity with SGLT-2 inhibitor drugs can be an effective method in the complex therapy of this disease. However, it is not universal and has its limitations and risks. Additional studies are needed to study the long-term safety and efficacy of these drugs, including in difficult clinical scenarios.

Overweight and obesity are the main risk factors for the development of a number of diseases, such as hypertension, type 2 diabetes, cardiovascular diseases, dyslipidemia, osteoarthritis, obstructive sleep apnea, nonalcoholic fatty liver disease, and other diseases [18,19]. Moderate weight loss (5% of body weight) can improve glycemic control and insulin homeostasis and moderate cardiovascular risk factors associated with overweight and obesity [1,2,13]. There are now a variety of treatments for obesity, including diet, physical activity, drug therapy, and metabolic surgery. Although metabolic surgery is an effective treatment option for obese women, this method is invasive, quite expensive, available only to a limited population, and may have adverse consequences. Medications for weight loss in obesity include phentermine, topiramate/phentermine, lorcaserin, orlistat, naltrexone/bupropion, and liraglutide, often with some side effects with long-term use [1,2]. One of the newest trends in this important sector is the use of drugs that remove glucose from the urine. Such drugs include - SGLT-2 inhibitors, which are gaining more and more popularity among patients and doctors of various specialties. In this article, we will consider the main aspects of the treatment of obesity with the help of SGLT-2 inhibitor, their effectiveness, safety, and possible limitations.

Treatment of obesity with the help of medical drugs is part of a comprehensive approach in the fight against excess weight. Modern drugs for the treatment of obesity usually take into account physiological aspects that affect energy balance, satiety and metabolism and help control appetite and food intake. Below is a list and brief characteristics of drugs used in the treatment of obesity. Orlistat is a drug that works in the intestines and prevents the absorption of fat from food. It helps to reduce the number of calories entering the body and promotes the excretion of fat with faces. 

Phentermine-topiramate: This drug combination affects the central nervous system, increasing satiety and decreasing appetite. These medications can help control the amount of food you eat.

Bupropion-naltrexone: This drug combination also affects the central nervous system and helps control appetite and food intake.

Drugs in the class SGLT-2 inhibitors were developed to treat type 2 diabetes, but they can also promote weight loss by increasing the excretion of glucose from the body through the urine, thereby reducing excess calories. In addition, these drugs have a nephroprotective and cardioprotective effect, which is also necessary in the presence of diabetes. Medicines from the class of GLP-1 agonists, such as liraglutide and semaglutide, help reduce appetite and can affect weight loss by reducing food intake and changing eating habits. Treatment of obesity requires a complex approach taking into account the individual characteristics of the patient, taking into account such factors as age, gender, concomitant diseases, personal preferences, intolerance or hypersensitivity to food components, physical activity, and others [33,34,38,39,41,42,43,1-7].

What are SGLT-2 inhibitors?

Inhibitors of sodium-dependent glucose cotransporter type 2 (SGLT-2 inhibitor) are a class of drugs that affect the kidney's ability to remove glucose from the body. Inhibition of SGLT-2 inhibitor reduces the reabsorption of glucose from the glomerular filtrate in the proximal part of the renal tubules with a simultaneous decrease in sodium reabsorption, which leads to the elimination of glucose from the urine and osmotic diuresis. Thus, SGLT-2 inhibitor increases the delivery of sodium to the distal tubules, which increases tubuloglomerular feedback and lowers intraglomerular pressure. This, combined with osmotic diuresis, helps reduce volume overload, lower blood pressure, and preload and afterload, which can have a positive effect on cardiac remodeling and preservation of kidney function. The cardiac and renal benefit of SGLT-2 inhibitor is not solely dependent on the blood glucose-lowering effect and is not limited to patients with diabetes, as demonstrated in the DAPA-HF and DAPA-CKD studies.

The influence of SGLT-2 inhibitor on body weight in patients with diabetes and obesity: results of clinical trials.

To date, several important clinical trials have been conducted to study the efficacy of SGLT-2 inhibitor in the treatment of patients with type 2 diabetes and obesity. One such study, EMPA-REG OUTCOME, focused on studying the effectiveness of empagliflozin in the treatment of obesity and type 2 diabetes. The results of this study showed that empagliflozin not only improved glycemic control in patients with type 2 diabetes but also resulted in a statistically significant reduction in body weight compared to placebo. The EMPA-REG OUTCOME study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose) was aimed at evaluating the effect of empagliflozin, one of the representatives of the class of SGLT-2 inhibitor, on cardiovascular events and treatment outcomes in patients with type 2 diabetes type and high cardiovascular risk [44-48].

Key outcomes related to obesity treatment in the EMPA-REG OUTCOME include the following

Patients taking empagliflozin had a significant loss of body weight compared to the control group (which received a placebo). Empagliflozin also resulted in a statistically significant reduction in glycated hemoglobin (HbA1c) in patients with T2DM, indicating improved glycemic control. The study also found positive effects of empagliflozin on other cardiometabolic parameters such as blood pressure and lipid profile [44-48].

EMPA-REG OUTCOME was conducted by a large international group of investigators and included 7,020 patients with type 2 diabetes who were at high risk of cardiovascular events. The patients were randomly divided into two groups: one was assigned to receive empagliflozin and the other a placebo, in addition to their usual treatment for diabetes and other co-morbidities [44-48].

The main results of the EMPA-REG OUTCOME study

The empagliflozin group had statistically significantly fewer incidents of cardiac events, strokes, and cardiac death compared to the placebo control group. There was a significant decrease in glycosylated hemoglobin (HbA1c) in patients taking empagliflozin. The safety and tolerability of empagliflozin were adequate.

Results for body weight and obesity

One of the important subgroups of EMPA-REG OUTCOME was obesity and body weight parameters. The results of this study showed that empagliflozin resulted in a statistically significant and clinically important reduction in body weight compared to the placebo group. On average, patients taking empagliflozin lost about 2-3 kilograms of weight over 3-6 months. This reduction in body weight was statistically significant and contributed to the improvement of obesity parameters of the study participants [1,2,3,14,20].

The mechanism of action of empagliflozin on body weight

The mechanism of action of empagliflozin on body weight is related to its effect on the kidneys and glucose metabolism. Empagliflozin blocks the activity of sodium-dependent glucose cotransporter type 2 (іSGLT2) in the kidneys, which promotes the excretion of more glucose in the urine. This leads to a loss of calories and a decrease in appetite, which can contribute to weight loss. Therefore, the EMPA-REG OUTCOME study confirmed the effectiveness of empagliflozin SGLT-2 inhibitor in reducing body weight and improving obesity parameters in patients with type 2 diabetes. This result indicates the potential benefit of this class of drugs in the treatment of obesity, especially in patients with type 2 diabetes and high cerebrovascular risk. However, before prescribing empagliflozin or other SGLT-2 inhibitor in obese patients, it is important to carry out an individual assessment of the risks and benefits of these drugs. [14,18,19,20,44-48]. Another study, known as CANVAS (Canagliflozin Cardiovascular Assessment Study), evaluated the effects of canagliflozin, a drug in the class of SGLT-2 inhibitor, on cardiovascular events and outcomes in patients with T2DM and high cardiovascular risk. The results of this study also confirmed the drug's ability to reduce body weight and improve the participants' metabolic profile [4,8,17,24-29,31,39].

Patients were randomized into two groups: a group that received canagliflozin (different doses of the drug were considered) and a control group that received a placebo. The primary outcome measure was a composite endpoint including cardiac death and heart attacks or strokes. The study also evaluated the effect of canagliflozin on other important endpoints, such as overall mortality, hypoglycemia, general condition of patients, changes in glycosylated hemoglobin (HbA1c), weight loss, and other parameters. However, the primary objective of the study was to determine the safety and efficacy of canagliflozin in terms of cardiovascular events, not to treat obesity as a disease itself. SGLT-2 inhibitors, such as canagliflozin, are commonly used to treat type 2 diabetes and help lower blood glucose levels, reduce insulin resistance, and reduce body weight. These effects may be beneficial in obese individuals, especially if obesity is accompanied by type 2 diabetes or other cardiovascular risk factors. Thus, the study results indicated the benefit of canagliflozin in reducing cardiovascular events in patients with type 2 diabetes and high cardiovascular risk. [4,8,17,24-29,31,39]. Effectiveness of SGLT-2 inhibitors in treatment obesity in patients without diabetes.

Inhibitors of SGLT-2 inhibitor have proven to be effective in improving glycemic control and reducing body weight in patients with type 2 diabetes. However, the efficacy and safety of weight loss in overweight or obese adults without diabetes remain unclear.

To study this important topic, the researchers conducted a literature review, namely, a wide search for randomized clinical trials (RCT) in Medline (Ovid SP), Embase (Ovid SP), Cochrane Central Register of Controlled Studies (Ovid SP), for studies published from the time the databases were created until February 20, 2021.  Next, we present the results of an RCT on the efficacy and safety of SGLT-2 inhibitor in overweight or obese adults without diabetes.

SGLT-2 inhibitors, including canagliflozin, dapagliflozin, empagliflozin, and others, have proven effective in the treatment of type 2 diabetes and are considered effective in reducing body weight [1,2,3,16,23,35-37]. According to the literature, weight loss can not only reduce the risk of cardiovascular and metabolic diseases but also improve fertility. A prospective cohort study in Boston showed that short-term weight loss (3 kg) was associated with a higher proportion of metaphase II (MII) oocytes retrieved in obese or overweight women, who underwent the procedure of assisted reproduction [15]. This meta-analysis of 872 subjects showed that SGLT-2 inhibitors can reduce body weight in overweight or obese adults without diabetes, and this result is similar to a previous meta-analysis that showed a reduction in body weight (MD: 1, 74 kg, 95% CL: -2.03 to -1.45) compared with placebo in type 2 diabetes. In addition, SGLT-2 inhibitors also appeared to be beneficial in reducing BMI but had no positive effect on waist circumference control compared to placebo. Subgroup analysis showed that the weight-reducing effect of canagliflozin and serializing may not be dose-dependent.

SGLT-2 inhibitors were generally well tolerated in previous studies in the type 2 diabetes population [21,23]. The main adverse reactions were genital fungal infection and urinary tract infection [24,25]; these side effects were classified by severity as mild or moderate. Compared with placebo, SGLT-2 inhibitors were associated with significant differences in the incidence of genital mycotic infection and nausea, with a particular focus on higher rates of vulvovaginal mycotic infection in women in the SGLT-2 inhibitor group, which may be related to increased urinary glucose excretion, and as a result - increased growth of vulvovaginal Candida [30]. In this study, the researchers concluded that canagliflozin treatment was associated with increased vaginal Candida colonization and the development of symptomatic vulvovaginal adverse events in women with type 2 diabetes. It should be added that the age of women ≤55 years was associated with an increased risk of developing genitourinary and fungal infections, according to the data of this study [1,2,3,16,23,35-37].

Mechanisms of body weight reduction. The exact mechanisms by which SGLT-2 inhibitors reduce body weight have not been fully understood. Recent clinical studies have shown that the weight loss effect observed with SGLT-2 inhibitors contributed to increased energy loss through urinary glucose excretion and moderate osmotic diuresis [23,27]. SGLT-2 inhibitor treatment may also alter body composition through energy loss and osmotic efflux, which have been associated with fat mass [27]. Cefalu and colleagues [8] demonstrated that the weight loss observed with canagliflozin in type 2 diabetes was mainly due to a reduction in fat mass, with a slightly greater loss of visceral fat compared with subcutaneous fat. Lowering the leptin-adiponectin ratio with remogliflozin has been reported to improve metabolic health in overweight or obese adults without diabetes, suggesting this as an additional mechanism for weight reduction with SGLT-2 inhibitors [27,29]. In addition, SGLT-2 inhibitors induced glycogen depletion signals in the liver and activated the liver-brain-adipose tissue axis, which led to the activation of protein kinase A in adipocytes, thereby causing fat reduction and weight loss [30-39]. Further studies are needed to confirm potential mechanisms [1,2,3,16,23,35-37].

 A study by Sarich and colleagues [4,8,17,24-29,31,39] found that canagliflozin increased 24-hour urinary glucose excretion in a dose-dependent manner and reduced body weight, but was not associated with significant changes in plasma glucose or insulin levels in obese nondiabetic adults. Side effects were transient and mild, with no reports of hypoglycemia. Lundkvist and colleagues [22,23] reported a study of obese adults without diabetes who received dapagliflozin 10 mg once daily and exenatide 2 mg once weekly achieved a mean weight loss of -4.5 kg after 24 weeks and -5.7 kg over 28 weeks, weight loss was mostly due to reduction in subcutaneous and visceral abdominal adipose tissue. This treatment also had a greater effect on glycemic control, prevalence of prediabetes, and systolic blood pressure. This suggests a potential role in the prevention of type 2 diabetes and cardiovascular disease in this population.

There are some limitations to this analysis. A major limitation is that only six studies with small sample sizes and short follow-up periods were included in the analysis, sample sizes of included studies ranged from 18 to 376, and follow-up periods ranged from 2 to 26 weeks, potentially leading to unstable estimates of treatment effects. In addition, the rate of discontinuation of SGLT-2 inhibitors was high due to some safety concerns. Furthermore, this meta-analysis showed that ACE inhibitors can reduce mean body weight by 1.42 kg in overweight or obese adults without diabetes, but the clinical and prognostic benefits of weight change were limited based on previous studies [1,2,3,16,23,35-37]. Thus, larger sample sizes with longer follow-ups are needed to elucidate the long-term benefits and risks of SGLT-2 inhibitors in the treatment of overweight or obese adults without diabetes. In addition, this study included only monotherapy and placebo-controlled RCT, and the differences between individual SGLT-2 inhibitors cannot be compared due to the lack of head-to-head studies.

Resume

According to this meta-analysis, SGLT-2 inhibitor drugs reduced body weight with statistical significance in overweight or obese adults without diabetes. Given the limited weight loss and potential harm, SGLT-2 inhibitors should be considered as an alternative treatment for weight loss in addition to lifestyle interventions in these patient groups, in the setting of low risk of sexually transmitted infections and urinary tract infections. For a more in-depth study of this current topic, further studies with large samples and longer periods are needed. The effectiveness of SGLT-2 inhibitors in the treatment of obesity: benefits and limitations. Benefits include: Decrease in body weight. Studies have shown a statistically significant effect on reducing body weight of the participants. Improvement of the metabolic profile. SGLT-2 inhibitors can improve glycemia, reduce the level of glycosylated hemoglobin, and improve insulin resistance. Possibility of treatment of concomitant diseases. Obese individuals often have other medical problems, such as diabetes, hypertension, and dyslipidemia, and SGLT-2 inhibitors may have a positive effect on these conditions [1,2,3,16,23,35-37].

Safety and side effects of SGLT-2 inhibitors

Despite the positive aspects associated with the use of SGLT-2 inhibitors, they may have certain side effects. These include urinary tract infections, hypotension, hyperkalemia, and others [24,25,26,27,28]. It is important to discuss all possible risks and benefits of taking these drugs before prescribing them.

Although SGLT-2 inhibitors may be effective for many obese patients, they are not suitable for everyone. These drugs can be ineffective or even dangerous for people with certain diseases, as well as for pregnant and nursing mothers.

Limitations include: Some patients may experience the following side effects: urinary tract infections, frequent fungal lesions of the genitals, hypotension, hyperkalemia, and others [30]. SGLT-2 inhibitors can be quite expensive and inaccessible to patients.

Treatment of obesity with SGLT-2 inhibitors can be an effective method in the complex therapy of this disease. However, it is not universal and has advantages and limitations. According to the literature, SGLT-2 inhibitors were useful in reducing BMI but did not have a positive effect on waist circumference control compared to placebo.

A significant advantage of these drugs is weight loss, which can not only reduce the risk of cardiovascular and metabolic diseases but also improve fertility. In an RCT, short-term weight loss (3 kg) was associated with higher oocyte yield in obese or overweight women without diabetes undergoing assisted reproduction. It should be added that the weight loss effect observed with SGLT-2 inhibitors contributed to increased energy loss through urinary glucose excretion and moderate osmotic diuresis. were associated with fat mass. Unconditional benefits of weight loss with remogliflozin include an additional mechanism of lowering the leptin-adiponectin ratio and improving metabolic health in overweight or obese adults without diabetes. In addition, inhibition of SGLT-2 inhibitors has been shown to trigger glycogen depletion signals in the liver and activate the liver-brain-adipose tissue axis, leading to the activation of protein kinase A in adipocytes, thereby causing fat reduction and weight loss.

The main side effects of taking SGLT-2 inhibitors were genital fungal infection and urinary tract infection; these side effects were mild to moderate. According to RCT, treatment with canagliflozin was associated with an increase in vaginal Candida colonization and the development of symptomatic vulvovaginal adverse events in women with type 2 diabetes. It should be added that the age of women ≤55 years was associated with an increased risk of developing genitourinary and fungal infections. It is important to discuss the possible risks and side effects with the patient and take into account the individual characteristics of each patient. However, more studies are needed to study the long-term safety and efficacy of these drugs, including in difficult clinical scenarios.