Abstract
Context
Obesity is a chronic disorder with excessive accumulation and hypertrophy of adipose cells. Selective sodium-glucose cotransporter-2 (SGLT2) Inhibitor has shown an effect of weight loss in several studies. However, weight loss in patients with obesity without diabetes remains unclear.
Objective
This systematic review aims to address the weight loss effects of SGLT 2 inhibitors in obese subjects without diabetes.
Methods
We incorporated search engines from Pubmed, EBSCO host, and Proquest. The inclusion criteria for this research were full-text, written in English, written in Bahasa Indonesia, reported the effect of SGLT 2 inhibitors for weight loss in obese patients, the design of the studies, outcomes, and the results of the study. We created a data extraction table to gather the required data for the review. The exclusion criteria for this study were incomplete outcomes, not full-text studies, case reports, literature review, and irrelevant studies.
Results
A total of 451 studies were identified from research database. There are 7 studies eligible to be included in this review. Weight loss effects of SGLT2 Inhibitors were observed in all the studies included in this review.
Conclusion
SGLT2 inhibitor is an effective weight loss therapy in patients with obesity without diabetes.
Keywords: Obesity, SGLT2 Inhibitors, Weight Loss
Introduction
Obesity is a chronic disorder with excessive accumulation and hypertrophy of adipose cells (1). This condition is caused by multiple complex factors comprised of intrinsic and extrinsic factors (such as environmental, genetic, neural, endocrine components). However, the fundamental source is the imbalance of calories, in which the amount of calories consumed is larger than those expended (2). According to the World Health Organization (WHO), in 2016, there are more than 1.9 billion persons aged 18 years and over were overweight and obese, which comprised 13% of the world’s adult population (3). The rising body mass index (BMI) is a major health concern, especially for chronic non-communicable diseases, such as diabetes mellitus type 2, cardiovascular diseases, osteoarthritis, and some cancers. These conditions are not exclusively caused by genetics, eating styles, and sedentary life (3,4). Due to severe complications and the burden of subsequent diseases following obesity, there is a need to look for ways to reduce obesity, one of which is promoting weight loss.
Selective sodium-glucose cotransporter-2 (SGLT2) inhibitors provide an insulin-independent mechanism for improving blood glucose levels and are approved to treat type 2 diabetes. They promote glucose excretion in the urine (up to about 50%) by inhibiting the reabsorption of glucose from the urine into the proximal tubules of the kidney (5). The degree of glycosuria is proportional to plasma glucose above the threshold (6).
SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, etc.) and glucagon-like peptide-1 receptor agonists (GLP1RA, exenatide, liraglutide, semaglutide, etc.) are both used to treat type 2 diabetes, but they may also cause weight loss. In addition, the effects of these drug classes on blood glucose and weight are retained for several years (5,7,8). Weight loss due to SGLT2 inhibitors has been consistently observed in several studies of type 2 diabetes regardless as a monotherapy or in combination with other hypoglycemic therapy (6). Currently, only a few studies have looked at the weight loss effects of SGLT2 inhibitors in obese subjects without type 2 diabetes. Thus this systematic review aims to address the knowledge about weight loss effects of SGLT 2 inhibitors in obese subjects without diabetes.
Methods
Research design
This research did not involve human subjects; therefore, it was exempt from ethical clearance. We used systematic review to find the total effect of the SGLT 2 inhibitors for weight loss in obese patients. PRISMA 2020 guideline was used for this systematic review.
Data sources and search strategy
We incorporated search engines from Pubmed, EBSCO host, and Proquest. The inclusion criteria were articles that performed empirical studies (primary articles), articles that reported SGLT 2 for weight loss in obese patients, articles published in peer-reviewed journals, the study participants were obese patients. MeSH Terms used were (((“Sodium-Glucose Transporter 2 Inhibitors”[MeSH]) OR (((((((((((((Sodium Glucose Transporter 2 Inhibitors) OR SGLT-2 Inhibitors) OR SGLT 2 Inhibitors) OR SGLT2 Inhibitors) OR Sodium-Glucose Transporter 2 Inhibitor) OR Sodium Glucose Transporter 2 Inhibitor) OR SGLT2 Inhibitor) OR Inhibitor, SGLT2) OR Gliflozins) OR Gliflozin) OR SGLT-2 Inhibitor) OR Inhibitor, SGLT-2) OR SGLT 2 Inhibitor))) AND (((“Obesity, Abdominal”[MeSH]) OR (((((((((((Abdominal Obesities) OR Obesities, Abdominal) OR Central Obesity) OR Central Obesities) OR Obesities, Central) OR Obesity, Central) OR Abdominal Obesity) OR Obesity, Visceral) OR Visceral Obesity) OR Obesities, Visceral) OR Visceral Obesities)))
Study selection and data extraction
The team conducted this systematic review consisting of three general practitioner doctors. All authors screened searched results firstly from the titles and abstracts of all searching results. Full papers were then retrieved for further review if relevant. The articles included should report the effect of SGLT-2 inhibitor on weight loss in obese patients. We found a total of 5087 articles from different search engines.
The inclusion criteria for this research were full-text, written in English, written in Bahasa Indonesia, reported the effect of SGLT 2 inhibitors for weight loss in obese patients, the design of the studies, outcomes, and the results of the study. To remove duplicates and manage the bibliography of the selected literature, we utilized Mendeley™. We created a data extraction table to gather the required data for the review. The exclusion criteria for this study were incomplete outcome, not full-text studies, case reports, literature review, and irrelevant studies.
Risk of bias
We used RoB 2 for assessing our systematic review articles in this study. RoB 2 is structured into a fixed set of domains of bias, focus\sing on different aspects of trial design, conduct, and reporting. All the studies are randomized controlled trial study (RCT).
Results
Characteristics of studies
A total of 451 studies were identified from research database (Fig. 1). After removing the duplicate records, 205 records were screened, and 16 were assessed for eligibility. Seven studies were included in the review, after excluding 9 studies due to out of scope and insufficient detail. There are 7 studies published between November 2010 and November 2021 (Table 1) (9–15). All of the studies found were randomized controlled trials. There are 5 studies comparing the use of SGLT2 inhibitors with varying doses and placebo. The remaining 2 studies compared the use of SGLT2 inhibitors with other drugs compared to placebo.
Figure 1.
Process of article selection based on PRISMA 2020.
Table 1.
Results of included studies
| Author, Year | Title | Intervention | Study Design, Duration, Number of participants | Outcome | Adverse Effects | |
|---|---|---|---|---|---|---|
| Placebo Group | Intervention Group | |||||
| Bays et al, 2014(9) | Canagliflozin: Effects in Overweight and Obese Subjects Without Diabetes Mellitus |
Placebo vs. Canaglifozin (varying dose) | RCT, 12 weeks, n= 376 |
Canagliflozin produced reductions in body weight compared with placebo (least squares mean percent changes from baseline of -2.2%, -2.9%, -2.7%, and -1.3% with canagliflozin 50, 100, and 300 mg and placebo; P < 0.05 for all comparisons). | Placebo Group : Headache (8) Urinary tract infection (7) Upper respiratory tract infection (6) Diarrhea (6) |
Canagliflozin 50 mg Group : Urinary tract infection (10) Headache (8) Genital fungal infection (14) Canagliflozin 100 mg Group : Genital fungal infection (13) Headache (12) Urinary tract infection (8) Canagliflozin 300 mg Group : Genital fungal infection (22) Urinary tract infection (8) Upper respiratory infection (5) |
| Bays et al., 2020(10) | Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity |
Placebo vs. Licoglifozin (varying dose) | RCT 24 weeks, n=394 |
Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). Mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83%. | Placebo Group : Constipation (20.5) Diarrhea (19.2) Abdominal distension (14.1) |
Licogliflozin 2.5 mg qd Group : Diarrhea (18.4) Constipation (15.8) Flatulence (13.2) Licogliflozin 10 mg qd Group : Flatulence (21.1) Diarrhea (15.8) Constipation (10.5) Backpain (10.5) Licogliflozin 50 mg qd Group : Diarrhea (55.3) Flatulence (26.3) Constipation (18.4) Abdominal distension (13.2) Licogliflozin 150 mg dq Group : Diarrhea (68.8) Flatulence (29.9) Constipation (13) Abdominal distension (13) Licogliflozin 2.5 mg bid Group : Constipation (31.6) Flatulence (28.9) Diarrhea (26.3) Abdominal distension (18.4) Licogliflozin 5 mg bid Group : Diarrhea (20.5) Constipation (12.8) |
| Bays et al., 2020(10) | Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity |
Placebo vs. Licoglifozin (varying dose) | RCT 24 weeks, n=394 |
Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). Mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83%. | Placebo Group : Constipation (20.5) Diarrhea (19.2) Abdominal distension (14.1) |
Dyspepsia (12.8) Licogliflozin 25 mg bid Group : Diarrhea (39.5) Flatulence (28.9) Constipation (15.8) Licogliflozin 50 mg bid Group : Diarrhea (56.6) Flatulence (36.8) Abdominal distension (14.5) Upper abdominal pain (11.8) |
| He et al., 2019(11) | The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes | Placebo vs. Licoglifozin (varying dose) | RCT, 12 weeks, n=88 |
Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs. placebo (P < 0.001). | Placebo Group : Headache (36.4) Diarrhea (25) Oropharyngeal pain (13.6) Abdominal pain (11.4) |
Licoglifozin Group : Diarrhea (90.9) Flatulece (43.2) Abdominal pain (27.3) Abdominal distension (25) |
| Hollander et al., 2017(12) | Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial | Placebo vs Canaglifozin vs. Phentermine vs. Canaglifozin + Phentermine | RCT, 26 weeks, n=335 |
Canagliflozin (CANA) and phentermine (PHEN) provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference -6.9% [95% CI -8.6 to -5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss ≥5%. | Placebo Group : Upper respiratory tract infection (18.3) Tooth infection (4.9) Nasopharyngitis (4.9) Constipation (3.7) Insomnia (3.7) |
Canaglifozin 300 mg Group : Upper respiratory tract infection (13.1) Nausea (8.3) Pharyngitis (4.8) Fungal infection (4.8) Back pain (3.6) Penthermine 15 mg : Constipation (12.9) Nausea (7.1) Bronchitis (5.9) Upper respiratory tract infection (5.9) Influenza (4.7) Canaglifozin 300 mg + Phentermine 15 mg Group : Upper respiratory infection (10.8) Constipation (7.2) Dry mouth (6) Headache (6) Fungal infections (4.8) |
| Lundkvist et al., 2017(13) | Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes |
Placebo vs. Dapaglifozin + Exenatide | RCT, 24 weeks, n=50 |
Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (-4.5 and -5.7 kg) and total adipose tissue volume (-3.8 and -5.3 L). | Placebo Group : Local injection disorders (32) Nasopharyngitis (16) Headache (16) Decreased appetite (12) Urinary tract infection (4) Dapaglifozin 10 mg once daily + Exenatide 2 mg once weekly Group : Local injection disorders (44) Nasopharyngitis (36) Headache (32) Decreased appetite (32) Urinary tract infection (12) |
|
| Napolitano et al., 2014(14) | Exploring glycosuria as a mechanism for weight and fat mass reduction. A pilot study with remogliflozin etabonate and sergliflozin etabonate in healthy obese subjects |
Placebo vs. Remoglifozin vs Serglifozin | RCT, 12 weeks, n=30 |
Statistically significant decreases in body mass from baseline values to Week 8 were observed for RE (-7.6 kg) and SE (-6.1 kg), but these decreases were not significantly greater than the weight loss observed in the placebo group (-5.1 kg) (Table 2). Consistent with the results for body weight, all treatment groups exhibited a statistically significant decrease in fat mass as measured using both QMR and the 4C model. | Placebo Group : Headache (50) | Remoglifozin 250 mg Group : Headache (44) Serglifozin 1000 mg Group : Headache (33) |
| Ramirez-Rodriguez et al., 2018(15) | Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients with Prediabetes |
Placebo vs. Dapaglifozin | RCT, 12 weeks, n=24 |
After dapagliflozin administration, there were significant decreases in body weight (80.8±16.3 vs. 77.8±14.9 kg, p=0.019), body mass index (30.3±3.5 vs. 29.2±3.1 kg/m2, p=0.023), waist circumference (100.6±13.5 vs. 96.2±11.8 cm, p=0.003) | Placebo Group : Dizziness and Headache (?) |
Dapaglifozin 10 mg Group : Urinary tract infections (2/12) Low back pain (1/12) Dizziness and Headache |
Weight loss effects of SGLT 2 Inhibitors
Weight loss effects of SGLT2 Inhibitors were observed in all the studies included in this review (Table 2). Bays et al. (2014) compared placebo and varying doses of canagliflozin (50 mg, 100 mg, and 300 mg). The study found that Canagliflozin 100 mg leads to most weight loss compared to placebo (-1.6%, p<0.001). In another study (Bays, 2020) comparing placebo and licogliflozin with varying doses, it is reported that licogliflozin 150 mg once daily (-4.16% 95% CI: -6.71, -1.55) and licogliflozin 50 mg twice daily (-5.29%, 95% CI: -8.20, -2.25) leads to the most weight loss in the normoglycemic obese subject when compared to placebo. He et al. reported that in obese subjects with normoglycemic and dysglycemic, compared to placebo, licogliflozin 150 mg leads to weight loss as well (-5.7%, 80% CI: -6.52, -4.87). Furthermore, weight loss in the licogliflozin group is higher in the normoglycemic group (-2.09 % ,80% CI: -3.52, -0.93). Hollander et al. reported that the greatest weight loss compared to placebo was observed when canagliflozin 300 mg was administered with phentermine 15 mg (-6.9%, 95% CI: -8.6, -5.2). Lundkvist et al. discovered that dapagliflozin 10 mg once daily with exenatide 2 mg once weekly shows weight loss effects compared to placebo (-4.19%, 95% CI: -6.57,-1.92). Ramirez-Rodriguez et al. compared Dapagliflozin 10 mg and placebo with changes in body weight, respectively, -1.0 kg and -3.0 kg (P<0.05). Napolitano compared placebo and two types of SGLT2 Inhibitors, remogliflozin, and sergliflozin. Remogliflozin demonstrated a greater weight loss effect compared to placebo (-2.5 kg, CI: -5.6, +0.6, p=0.105).
Table 2.
Weight loss changes among treatment groups
| Study | Duration | N | Treatment Arms | Weight loss effects (BW Changes vs. Placebo) |
|---|---|---|---|---|
| Bays, 2014 | 12 weeks | 376 | Placebo | |
| Canagliflozin 50 mg | -0.9% (P=0.031) | |||
| Canagliflozin 100 mg | -1.6% (P<0.001) | |||
| Canagliflozin 300 mg | -1.4% (P<0.001) | |||
| Bays, 2020 | 24 weeks | 394 | Placebo | |
| Licogliflozin 2.5 mg qd | N/A | |||
| Licoglifllozin 10 mg qd | N/A | |||
| Licoglifozin 50 mg qd | N/A | |||
| Licogliflozin 150 mg qd | -4.16% (95% CI: -6.71, -1.55) | |||
| Licogliflozin 2.5 mg bid | N/A | |||
| Licogliflozin 10 mg bid | N/A | |||
| Licogliflozin 50 mg bid | -5.29% (95% CI: -8.20, -2.25) | |||
| Licogliflozin 150 mg bid | N/A | |||
| He, 2019 | 12 weeks | 88 | Placebo | |
| Licogliflozin 150 mg | -5.7% (80% CI: -6.52, -4.87) (Obesity with normoglycemic AND dysglycemic group vs. Placebo) | |||
| -2.09 % (80% CI: -3.52, -0.93) (Licoglifozin group, normoglycemic vs. dysglycemic group) | ||||
| Hollander, 2017 | 26 weeks | 335 | Placebo | |
| Canagliflozin 300 mg | -1.3% (95% CI: -3.1, 0.4) | |||
| Phentermine 15 mg | -3.5% (95% CI:-5.3, -1.8) | |||
| Canagliflozin 300 mg + Phentermine 15 mg | -6.9% (95% CI: -8.6, -5.2) | |||
| Lundkvist, 2016 | 24 weeks | 50 | Placebo | |
| Dapagliflozin 10 mg once daily + Exenatide 2 mg once weekly | -4.19% (95% CI: -6.47, -1.92) | |||
| Ramirez-Rodriguez, 2018 | 12 weeks | 24 | Placebo | |
| Dapaglifozin 10 mg | -1.0 kg (Placebo) vs. -3.0 kg (Dapaglifozin) (P<0.05) | |||
| Napolitano, 2014 | 8 weeks | 30 | Placebo | |
| Remogliflozin etabonate 250 mg | -2.5 kg (-5.6, +0.6) P=0.105 | |||
| Sergliflozin etabonate 1000 mg | -1.0 kg (-3.9, +2.0) P=0.511 |
Other effects
Bays et al. (2014) found that from baseline to Week 12, canagliflozin 50, 100, and 300 mg and placebo were associated with mean percent changes in LDL-C of 4.2%, 7.5%, 10.0%, and 6.4%, respectively. Another study by Bays et al. (2020) found that clinically relevant and statistically significant raw mean changes in HbA1c over 24 weeks were seen only with the two highest once-daily doses and the highest twice-daily dose of licogliflozin versus placebo in patients with T2DM. Overall, systolic blood pressure (SBP) tended to be reduced from baseline in all licogliflozin treatment groups versus placebo following 24 weeks of treatment. Statistically significant adjusted mean changes were observed for licogliflozin 50 mg qd. Significant reductions in triglycerides were seen with 50 mg qd.
He et al. found that treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs. placebo and improved metabolic parameters such as significantly reduced postprandial glucose excursion, reduced insulin levels (80%; P < 0.001) and increased glucagon. In patients with T2DM, a single dose of licogliflozin 300 mg in the morning before an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% and suppressed insulin by 90%. Hollander et al. found that canagliflozin reduces systolic blood pressure. No notable changes were found in fasting plasma lipids with canagliflozin.
Dapagliflozin also caused a reduction in HbA1C and blood pressure. No significant changes in high-density lipoprotein cholesterol were observed in participants in either treatment group. Low-density lipoprotein cholesterol and triglyceride decreased significantly. A statistically significant treatment-related effect of remogliflozin etabonate (RE) and sergliflozin etabonate (SE) on urine glucose excretion, with remogliflozin etabonate producing greater urine glucose excretion than SE, as expected from the differences in drug exposure and potency of the two inhibitors.
Rodriguez et al. found that dapagliflozin caused reduced fasting glucose and uric acid, with a tendency to increase insulin sensitivity. Dapagliflozin administration in patients with prediabetes decreased body weight, body mass index, waist circumference, fasting glucose, and uric acid, with a tendency to increase insulin sensitivity without changes in insulin secretion.
Safety and adverse events
A study by Bays et al. (2014) showed no significant differences in the overall incidence of adverse events among treatment groups (Bays et al., 2014). The incidence of serious adverse events was found in treatment groups of Canagliflozin with a higher dose (300 mg), which also causes a higher rate of genital fungal infection (22%). Canagliflozin was also used in Hollander et al. in their study, but there was no significant difference between overall adverse events (59.5% and 57.3%) with placebo (Hollander et al., 2017). The incidence of upper respiratory infection was more common in the placebo group (18.3% and 13.1%).
In Bays et al. (2020) and He et al. (2019), Licogliflozin caused adverse events; there are no significant differences between placebo and licogliflozin treatment groups. The most adverse effects were gastrointestinal disorders ranging from 33%-68% and infections (21%-45%). The adverse effects on gastrointestinal systems were diarrhea (the most common), flatulence, constipation and abdominal distension.
The use of Dapaglifzolin in Lundkvist et al. study increased the incidence of nasopharyngitis, headache, decreased appetite, and urinary infection. Two participants suffered from serious adverse events (head trauma and dyspnea). Local reaction was more commonly found than systemic adverse events. In a study by Ramirez-Rodriguez AM et al., dapagliflozin only causes mild symptoms: urinary tract infection (16.7%) and low back pain (8.3%).
Napolitano et al. used Remogliflozin etabonate and Sergliflozin etabonate, there were no serious adverse effects. The most common symptoms were headache, which occur in 44% of Remoglifozin Group, 33% of Serglifozin Group, and 50% of Placebo Group.
Risk of bias
The risk of bias summary was presented in Figure 2. Most of the studies were at low risk of bias.
Figure 2.
Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.
Discussion
SGLT are forms of active cotransporters localized in the brush border on S2 and S3 segments of proximal renal tubules (16). It works by reabsorbing the filtrated urinary glucose and preventing its excretion. Cell membranes are composed of lipids, which are impermeable to the absorption of polar compounds, such as glucose. In order to do so, the transport of glucose is facilitated by glucose transporter in the form of carrier protein. The transport of glucose in the kidney is facilitated by SGLT2 and SGLT1. SGLT2 catalyzed the active transport of glucose against concentration gradient along with coupled absorption of sodium across luminal membrane (16,17). The concentration of sodium inside the cell is maintained by the Na K ATPase in the basolateral membrane. Glucose inside the cell can passively diffuse out along the concentration gradient via GLUT2 (glucose transporter type 2) of the basolateral membrane into the blood. SGLT2 is responsible for 90% of reabsorbed glucose, whereas the remaining 10% is done by SGLT1. SGLT1 is located in mostly small intestine, whereas SGLT2 is located almost exclusively in the kidney. SGLT2-inhibitors work specifically in these active cotransporters, resulting in urinary glucose excretion, leading to lower levels of blood glucose. The mechanism of how this class of medication works is suitable for patients with type 2 diabetes because it is independent of insulin and blood glucose level, thus a lower risk of hypoglycemia (16). As a result of urinary glucose excretion, resulting in a calorie deficit, SGLT2 inhibitors also affect weight loss.
SGLT2 inhibitors directly reduce body weight by removing glucose (calorie loss) in the kidneys. SGLT2 inhibitors are glucose-dependent and can excrete approximately 60-100 g of glucose per day in the urine (18). Despite the calorie loss effects of SGLT2 Inhibitors, it causes less weight loss than expected due to an adaptive increase in energy intake, including compensatory increases in appetite/caloric intake (19). Hence combining SGLT2 inhibitors and other drugs that have weight loss effects with different mechanisms may be an effective approach for sustainable weight loss in the long term (18).
Glycosuria due to the SGLT2 inhibitors leads to lower plasma glucose and insulin levels, followed by increased fasting and post-meal glucagon concentration. Along with hormonal changes and the reduction of glucose concentration, lipid storage is mobilized to be used as an energy substrate. The body’s metabolism shifts towards utilizing fat for energy production. The metabolic adaptation towards the persistent excretion of glucose in the kidney includes: increased gluconeogenesis, suppression of tissue glucose disposal and glucose oxidation, accelerated lipolysis, increased fat oxidation, and enhances ketogenesis. The overall result of these metabolic changes resembles a fasting state, which will cause the loss of fat mass and weight in the long run (19).
As mentioned before, the combination of SGLT2 Inhibitors with other drugs that work with different mechanisms may be an effective approach for weight loss. The studies included in this systematic review all resulted in weight loss compared to placebo, 5 studies used only SGLT2 inhibitors, and 2 other studies explored combination therapy.
Hollander et al. studied the coadministrations of canagliflozin and phentermine compared with placebo. Phentermine is a sympathomimetic amine anorectic that plays a role in stimulating the satiety centers in the brain through the upregulation of dopamine, noradrenaline, and serotonin (20). The study concluded that the combination of canagliflozin and phentermine was superior in terms of weight loss when compared to placebo or canagliflozin or phentermine alone. The effect of canagliflozin and phentermine was additive and perhaps synergistic. It is possible that the stimulation of the satiety center by phentermine might counteract the adaptive increase of appetite/caloric intake (12).
Another study by Lundkvist et al. explored the co-administration of dapagliflozin and exenatide, a glucagon-like-peptide-1 receptor antagonist (GLP-1 RAs). Like SGLT2 inhibitors, GLP-1RAs are approved treatment for adult patients with type 2 diabetes mellitus. GLP-1RAs are administered through injection; in the case of exenatide, it is administered weekly. It stimulates GLP-1 receptors in the pancreas, enhancing insulin release and reducing glucagon release. Furthermore, the activation of GLP-1 receptors in the central nervous system and gastrointestinal tract results in reduced appetite and slower gastric emptying (21). The study demonstrated a significant weight loss difference compared to placebo. Like phentermine, the exenatide effect of reduced appetite and delayed gastric emptying may be synergistic and able to counteract the compensatory appetite increase. However, the study did not contain a monotherapy arm, thus the additive effect cannot be evaluated further.
The adverse event caused by most SGLT-2 inhibitors was due to increased urinary glucose leading to a higher incidence of genital fungal infection, particularly in women. The presence of headaches might be due to increased intravascular volume and hypoglycemia. Studies by Bays et al. (2014; 2020) showed increased adverse events, particularly infection in treatment with higher doses compared to lower doses and placebo (9,10). However, the studies did not conduct a more thorough evaluation regarding the adverse events.
In conclusion, SGLT2 inhibitor is an effective weight loss therapy in patients with obesity without diabetes,as found in the studies included in this systematic review. SGLT2 inhibitors remove glucose through urine, increasing calorie loss, which eventually leads to weight loss. This condition mimics the state of prolonged fasting. However, the body adapts to this condition through an increase in appetite/calorie intake, thus resulting in less weight loss.
This adaptive mechanism can be counteracted by combination therapy, as demonstrated using phentermine and GLP-1RA. Both reduce appetite, and perhaps the weight loss effect might be synergistic when used together with SGLT2 inhibitors. Our studies included larger sample sizes compared to previous studies by Zheng et al. The mechanism of SGLT2 inhibitors for weight loss is further discussed in this study, including the potential of using combination therapy (22). Nevertheless, further studies are needed to explore whether SGLT2 inhibitors with other drugs might have an additive or synergistic effect on weight loss.
Conflict of interest
The authors declare that they have no conflict of interest.
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