Introduction

For the last few decades obesity has constituted a growing worldwide public health issue that affects the risk and prognosis of several conditions, including cardiovascular disease (CVD), metabolic syndrome (MetS), type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), COVID‑19, and cancer.^1-5 According to the World Health Organization data, in 2016 more than 1.9 billion adults were overweight (body mass index [BMI] between 25 and 30 kg/m²), among whom more than 650 million were obese (BMI >30 kg/m²).⁶ Global trends in T2D parallel those of obesity, and an estimated 422 million individuals were affected as of 2014. The strong causal relationship between these 2 conditions is mediated through the interaction of a variety of genetic and environmental factors that culminate in the development of systemic insulin resistance and eventually β-cell failure; hence the recently coined term “diabesity.”^7-9

As the tide of obesity and its complications is on the rise, there is an urgent need for new drugs with weight‑lowering and beneficial metabolic properties.¹⁰ Obesity and obesity‑related disorders, such as MetS, prediabetes, T2D, NAFLD, and CVD complications, as well as the increased prevalence of certain types of cancer make this need more than mandatory. Lifestyle modifications, such as decreased calorie intake and increased physical activity play a key role in combating obesity but are not always very easy to pursue.¹¹ There are several weight‑lowering drugs, mainly lorcaserine, phentermine, topiramate, and glucagon‑like peptide‑1 (GLP‑1) receptor agonists, but their use is restricted by their adverse effects and limited effectiveness. Bariatric surgery offers a more drastic and more lasting weight‑lowering potential, and it may reverse prediabetes and T2D in a significant proportion of patients.¹⁰ However, bariatric surgery, while offering the effective solution regarding severe obesity, is also associated with severe adverse effects.^12,13

Sodium‑glucose cotransporter‑2 (SGLT‑2) inhibitors are a relatively new class of antidiabetic drugs, which act at the level of the renal proximal tubule, causing glucosuria. Apart from the glucosuric effects, they seem to exert pleiotropic biological effects, which are not directly attributable to the reduction of hyperglycemia, such as the reduction of cardiovascular mortality, heart failure (HF) hospitalizations, and hard renal outcomes. This has led to a gradual generalization of the indications for individual SGLT‑2 inhibitors outside of the frame of antihyperglycemic therapy or cardiovascular risk reduction among patients with T2D. They are now indicated for patients with HF with preserved (empagliflozin) and reduced ejection fraction (EF) (empagliflozin, dapagliflozin), as well as chronic kidney disease (CKD) of etiology other than diabetic kidney disease, such as ischemic or immunoglobulin A nephropathy, focal segmental glomerulosclerosis, chronic pyelonephritis, and chronic interstitial nephritis (dapagliflozin).¹⁴ Furthermore, their unique mode of action, which results in a glucosuria‑induced net caloric loss, renders the agents of these category attractive candidates for obesity therapy.

Very few reviews in the literature have discussed holistically the therapeutic potential of SGLT‑2 inhibitors in obesity and its associated complications.¹⁵ In this narrative review, we aim to 1) present the mechanisms of action of SGLT‑2 inhibitors, with a special focus on obesity and its associated disorders; 2) appraise their therapeutic applications; 3) discuss adverse effects and tolerability issues, and 4) review potential future perspectives and challenges.

Literature search

In August 2022, a literature search of 2 bibliographical databases (MEDLINE and Scopus) was conducted to assess the effects of SGLT‑2 inhibitors on obesity. This search used the following terms: “sglt2 inhibitors” and “obesity.” The search for the abovementioned terms yielded a total of 697 papers, most of which (539 results) were published between 2017 and 2022 (during the past 5 years). Of these 697 studies, 90 were excluded, as 79 dealt with issues such as chronic kidney disease (n = 20), type 1 diabetes (n = 15), COVID‑19 (n = 10), prediabetes (n = 9), dual inhibition of SGLT‑1 and SGLT‑2 (n = 8), merely heart failure (n = 6), merely hypertension (n = 5), asthma and obstructive sleep apnea (n = 3), or neurological diseases (n = 3), and the remaining 11 studies were not written in English (3 studies in Japanese, 2 in Spanish, 2 in French, 1 in Polish, 1 in Russian, 1 in Swedish, and 1 in Hebrew). In addition, there were 6 books and documents that were excluded, leaving a total of 601 studies included in this search.

Mechanisms of action of sodium‑glucose cotransporter‑2 inhibitors

An important milestone in the course of SGLT‑2‑inhibition–based therapy was the discovery of the antihyperglycemic effects of phlorizin, a substance isolated from the bark of an apple tree by Josef von Mering in 1886. Although he additionally postulated that the kidneys are its pharmacological target, it was not until the 1970s that inhibition of renal tubular glucose reabsorption was specified as the mechanism of action of phlorizin,¹⁶ while Rossetti et al¹⁷ demonstrated amelioration of insulin resistance and hyperglycemia after phlorizin administration in 1987. The development of the first orally absorbable, phlorizin‑derived SGLT‑1 and SGLT‑2 inhibitor was followed by a rapid discovery of more orally active agents, and in 2013 canagliflozin was the first SGLT‑2 inhibitor that received Food and Drug Administration (FDA) approval for the treatment of T2D, followed by dapagliflozin and empagliflozin in 2014.¹⁸ SGLT cotransporters are divided into 2 categories: SGLT‑1 and SGLT‑2 cotransporters. SGLT‑1 cotransporters are mainly located in the small intestine and are responsible for glucose absorption there and for the reabsorption of approximately 10% of the filtered glucose in the upper part of the renal proximal tubule. Their major mechanism of action is to delay glucose absorption in the small intestine, leading to a decrease in the serum postprandial glucose levels.¹⁹ SGLT‑1 cotransporters are also located in the kidneys, the brain, the heart, the trachea, the testis, and the prostate gland.¹⁹ On the contrary, SGLT‑2 cotransporters are mainly found in the proxy part of the renal proximal tubule, where they act by reabsorbing approximately 90% of the filtered glucose. Apart from the kidneys, SGLT‑2 cotransporters are expressed in the brain, the heart, the liver, the thyroid gland, the muscles, and the α pancreatic cells. Their major function in the kidneys is to impede renal glucose reabsorption, causing glucosuria.^20,21

Apart from lowering serum glucose levels, SGLT‑2 inhibitors have been documented to provide significant cardiovascular benefits in patients with T2D. Until now, there are 4 selective SGLT‑2 inhibitors with demonstrated cardiovascular benefit: empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin.²² The abovementioned drugs have been documented to control blood glucose levels, as well as to decrease body weight and reduce systolic and diastolic blood pressure.²³ Figure 1 summarizes the main biological actions of SGLT‑2 inhibitors, which are considered to contribute to their cardiorenal protective effects.