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Journal of Endocrinology & Metabolism

Review

Volume 14, Number 3, June 2024, pages 89-102

Pharmacological Treatment of Diabetes Mellitus: An Overview of New Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Diabetes Mellitus

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from a defect in insulin secretion or its action on tissues. The vast majority of individuals with diabetes have type 2 diabetes mellitus (T2DM), which is related to insulin resistance. The development of T2DM is largely influenced by modifiable environmental factors. These include inappropriate caloric balance leading to overweight or obesity, excessive intake of monosaccharides, and lack of physical activity. In recent decades, there has been a significant increase in the incidence of T2DM [1-3]. At the same time, new groups of drugs are emerging that not only control glycemic levels but also other risk factors, such as body weight.

Flozins, or sodium-glucose cotransporter 2 (SGLT2) inhibitors, are a relatively new and promising group of oral antidiabetic agents. They have been recognized in diabetology for their antihyperglycemic effect and have also been used in cardiology and nephrology to treat heart failure and chronic kidney disease [4-8]. In our review, we will focus on presenting the long-used flozins, as well as some promising new drugs in this group, and compare their effectiveness in the management of diabetes.

Among the drugs discussed in this article: canagliflozin, empagliflozin, and dapagliflozin have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of T2DM. Bexagliflozin was approved by the FDA in 2020 and is currently under registration process in Europe. However, enavogliflozin, janagliflozin and remogliflozin have recently been registered in China, Korea and India, respectively, but have not yet received approval from the FDA or EMA.

SGLT2 cotransporters belong to a large family of symporters responsible for facilitated transport of different solutes, aided by a positive sodium gradient [9, 10]. Two cotransporters can be distinguished in this group: SGLT1 and SGLT2. SGLT2 is responsible for the reabsorption of glucose from the proximal tubule of the nephron and is found almost exclusively in renal tissue. SGLT2 is capable of removing up to 97% of glucose from the primary urine [11-13]. The SGLT1 cotransporter, located further down the proximal tubule, reabsorbs any remaining glucose. Therefore, in healthy individuals all glucose is reabsorbed from the filtered primary urine because glucose excretion by the kidneys results in a loss of valuable calories for the body.

SGLT2 has a high capacity but low affinity for glucose, while SGLT1 has low capacity and high affinity.

The level of reabsorption is directly proportional to the concentration of glucose in the primary urine, but it is not unlimited. The maximum capacity of SGLT2 is reached at a glucose filtration rate of approximately 350 mg/min/1.73 m² [14, 15]. This is achieved at a glycemia of approximately 180 mg/dL. Above this threshold, the amount of filtered glucose exceeds the capacity of SGLT2, leading to glucosuria. To prevent chronic hyperglycemia from causing this process, the expression of SGLT2 cotransporter in the proximal tubule increases. The overexpression of SGLT2 is accompanied by an increase in the expression of the sodium-hydrogen exchanger 3 (NHE3) transporter, which is responsible for reabsorption of two-thirds of sodium filtered by the kidney [16-18]. It should be noted that SGLT2 itself not only transports glucose but also sodium at a 1:1 ratio.

Excessive reabsorption of sodium in the proximal tubule leads to a significant reduction in its concentration further down the loop of Henle and the distal tubule, which is misinterpreted by the macula densa as hypovolemia [19]. As a result, the secretion of adenosine by the macula densa is decreased. Adenosine typically induces vasodilation through A2 receptors, including those in efferent arterioles, but in afferent arterioles it causes vasoconstriction through A1 receptors [20]. Consequently, the decreased adenosine concentration causes afferent arteriole dilation and efferent arteriole constriction, both of which generate a high intraglomerular pressure. This leads to glomerular damage. Additionally, the juxtaglomerular cells activate the renin-angiotensin-aldosterone system (RAAS), contributing to hypervolemia and hypertension [21, 22].

Moreover, heightened filtration and reabsorption increases ATP and oxygen consumption. This can lead to local hypoxia, which results in the release of proinflammatory cytokines that can induce fibrosis and loss of glomerular function [23-25]. This chain of events can be prevented by SGLT2 inhibitors, thereby demonstrating their nephroprotective effect in diabetes (Fig. 1).

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Figure 1. Renal glucose reabsorption in the proximal tubule. SGLT2 cotransporter, located in the apical membrane of the early proximal tubule, absorbs up to 97% of glucose. The glucose is then transported back into the blood with the help of the GLUT2 transporter. The remaining glucose is absorbed by the SGLT1 cotransporter, located in the apical membrane of the late proximal tubule, and then enters the blood with the help of GLUT2/1 transporters. Therefore, under physiological conditions, almost 100% of glucose from the primary urine is reabsorbed. SGLT1/2: sodium-glucose cotransporter1/2; NHE3: sodium-hydrogen exchanger 3; GLUT1/2: glucose transporter1/2.

Theoretically, inhibiting SGLT2 should significantly reduce renal reabsorption capacity, causing glucosuria of more than 90% of daily glucose filtration. The level of glucosuria is directly proportional to the dose of flozin, but even at the maximum dose, the level of glucose excretion reaches at most about 50%. The paradox arises because inhibition of the SGLT2 cotransporter leads to the SGLT1 cotransporter taking over its role. Physiologically, the SGLT1 cotransporter is responsible for reabsorbing only several grams of glucose flowing through the proximal tubule, but its daily capacity can reach 120 - 140 g of glucose. This lowers the renal threshold to about 140 mg/dL [15, 26].

T-1095 was the first oral inhibitor of the SGLT2 cotransporter. However, due to its lack of selectivity, it also inhibited the SGLT1 cotransporter, resulting in gastrointestinal side effects [27-30]. At present, numerous selective new drugs in this category have been developed, with many more currently in the trial phase. Their application is not restricted to diabetes alone. Clinical trials of dapagliflozin [31-34] and empagliflozin [35-37] have shown significant benefits in patients at high cardiovascular risk. These include the treatment of heart failure, slowing down the progression of albuminuria in diabetic and non-diabetic kidney disease, and slowing down the overall progression of chronic kidney disease [38, 39] (Fig. 2).

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Figure 2. General mechanism of action of SGLT2 inhibitors. The green color marks benefits associated with the use of SGLT2 inhibitors, while white indicates the effects that can lead to benefits and/or adverse effects depending on the clinical situation, red shows potential adverse effects associated with the use of SGLT2 inhibitors. SGLT2 inhibition increases glucose and sodium excretion. Enhanced sodium excretion and decreased renal hyperfiltration delay the progression of chronic kidney disease. Increased glucose excretion leads to osmotic diuresis, which increases the risk of urinary tract infection, and sepsis. Increased diuresis reduces cardiac preload, thereby reducing the risk of cardiovascular events and mortality. In addition, there is a decrease in blood glucose levels, which reduces the need for insulin and glucotoxicity on the vascular endothelium, improving function of pancreatic beta cells. Glucose excretion leads to energy loss and weight loss, which lowers blood pressure and increases insulin sensitivity. It is important to note that while SGLT2 inhibitors do not cause hypoglycemia in monotherapy, they may increase the risk of occurrence of hypoglycemia when used in combination with other drugs that have hypoglycemic effect (e.g., insulin, sulfonylurea derivatives). SGLT2: sodium-glucose cotransporter 2; UTI: urinary tract infection; CV: cardiovascular; AKI: acute kidney injury; TG: triglycerides; HDL: high-density lipoprotein.

Endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis and is frequently accompanied by elevated oxidative stress and inflammatory response [40]. Correction of hyperglycemia by SGLT2 inhibitors, which results in increased urinary glucose excretion, leads to a reduction in glucotoxicity by decreasing advanced glycation end products (AGE) formation. This alleviates the oxidative stress and inflammatory response [41]. An in vitro study showed that SGLT2 inhibitors provide protection against high glucose-induced mitochondrial dysfunction. In particular, empagliflozin was observed to restore nitrite levels in cultured human umbilical vein endothelial cells during hyperglycemia. Furthermore, SGLT2 inhibitors, as well as antioxidant gene induction with sulforaphane, prevented high-glucose-induced endothelial dysfunction in mouse aortic tissue maintained in hyperglycemic medium [42].

Heart failure pathophysiology in T2DM arises through multiple mechanisms which affect cardiac contractility, relaxation and compliance. Diabetes accelerates the development of coronary artery disease, which may lead to myocardial infarction and structural changes [43]. Hyperactivation of the renin-angiotensin-aldosterone system (RAAS), as described above, contributes to hypertension, myocardial hypertrophy, inflammation, increased cardiac preload and afterload, and fibrosis. These factors inevitably lead to a decline in diastolic function [44]. Chronic hyperglycemia plays a key role in the development of heart failure in T2DM [45]. It results in the formation of non-enzymatic AGE, which negatively affect contractility and relaxation [46]. In physiological conditions, a healthy heart requires a significant amount of energy from a variety of substrates, including glucose and free fatty acids [47]. In hyperglycemic conditions, the ability of the myocardium to obtain energy from glucose is compromised, leading to a switch to fatty acid metabolism. This is less efficient, especially in the presence of increased oxygen demand, and is associated with elevated reactive oxygen species formation. Additionally, fatty acid metabolism affects calcium absorption, which in turn impairs diastolic function [48]. Ketone bodies may be a good alternative as a substrate for energy production. They have been observed to improve the metabolic efficiency of the heart, preventing the formation of reactive oxygen species and reversing ventricular remodeling [49]. Additionally, ketones exhibit anti-inflammatory properties by suppressing inflammasome subunit NLRP3 [50]. This suggests another potential therapeutic mechanism for SGLT2 inhibitors in the treatment and prevention of heart failure, which has been shown to induce euglycemic ketoacidosis.

Despite the tremendous benefits of SGLT2 inhibitors, these drugs are not without side effects. The direct effects of SGLT2 inhibitors are osmotic diuresis and plasma volume reduction, which are the main causes of adverse effects. These especially affect patients predisposed to genital or urinary tract infections, in most cases mild to moderate [51-55]. A very rare, but potentially fatal adverse effect is Fournier’s gangrene [56]. Euglycemic ketoacidosis has been observed in some cases [57-60]; however, this observation was not reported in the CREDENCE and DAPA-CKD trials.

The PubMed database was used for the analysis, and the criteria used depended on the number of publications available for a given flozin, resulting in a total of 395 publications that were further reviewed. For enavogliflozin and janagliflozin, the only primary criterion was the presence of the flozin name in the title. This resulted in nine and eight results, respectively. The publications were verified by rejecting off-topic papers, those lacking sufficient data for analysis, and studies conducted on non-human models. Finally, five papers on enavogliflozin and three on janagliflozin were included in this publication.

We applied the same criteria to papers published within the last 5 years to select relevant research on remogliflozin. Initially, 36 results were obtained, but after further verification, only three papers were used for analysis. For bexagliflozin, the criteria were expanded to include publications from the last 5 years and those with “diabetes” in the title. This resulted in 15 potential publications, eight out of which were eventually used in the analysis.

For canagliflozin, empagliflozin, and dapagliflozin, the primary criteria were expanded to include papers from the last 5 years that contain “diabetes” in the title and “HbA1c” in any field. This resulted in 47, 115, and 165 results, respectively. For canagliflozin, we further expanded the criteria to include “body weight” in any field, resulting in 19 papers. After analysis, we were able to include seven of these papers. In the case of empagliflozin and dapagliflozin, the criteria were expanded to include “body weight” and “systolic” content in all fields, resulting in 17 and 22 papers, respectively. After subsequent analysis, six papers were used in both cases. In the end, 38 papers were used to analyze the reduction of hemoglobin A1c (HbA1c), body weight and/or systolic blood pressure by each flozin (Fig. 3).

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Figure 3. Out of the 395 initially obtained results, 38 were eventually included in this review. The selection process involved scaling up with additional criteria based on the available pool of results for a given flozin, as well as a content analysis that rejected papers which were off topic, did not contain sufficient data, or involved non-human models. N: number of papers.

Enavogliflozin is a selective SGLT2 inhibitor. It is currently in clinical trials in Korea. It has more than 667-fold greater affinity for SGLT2 than for SGLT1 and a linear dose-effect relationship with both oral and intravenous administration [61]. To date, a few studies have been conducted to evaluate the safety and efficacy of enavogliflozin in the treatment of diabetes with good results. Enavogliflozin, like other drugs in this class, reduces HbA1c, body weight and blood pressure in patients (Table 1) [62-66]. Studies comparing HbA1c reductions induced by enavogliflozin and dapagliflozin showed a slight advantage of the former. This makes enavogliflozin likely to be another promising new drug in this group for a wider group of patients [62-66].

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Table 1. Effectiveness of Enavogliflozin in Reducing HbA1c, Body Weight, and Systolic Blood Pressure

Janagliflozin is an oral selective SGLT2 inhibitor, chemically developed and patented in China [67], which has demonstrated good efficacy and safety [68-72], including in patients with coexisting cirrhosis and chronic kidney disease [73, 74]. Three studies have been conducted to determine the efficacy of janagliflozin in reducing HbA1c. The results showed concentration decrease after 24 weeks of therapy: -0.58% for the 25 mg and 50 mg dose [70], -0.8% (95% confidence interval (CI): -0.98% to -0.62%) for the 25 mg dose, and -0.88% (95% CI: -1.06% to -0.7%) for the 50 mg dose [71], and -0.78% for the 25 mg dose and -0.93% for the 50 mg dose [72], respectively. Statistically significant reductions were observed in fasting plasma glucose, body weight, and systolic blood pressure in all of these studies. Additionally, increases in high-density lipoprotein (HDL) and insulin sensitivity were observed compared to placebo. The trends in improvement of these variables were sustained during the 28-week extension period.

Bexagliflozin is a novel and highly potent SGLT2 inhibitor with more than 2,435-fold selectivity for SGLT2 over SGLT1 [75]. The FDA granted the first approval of bexagliflozin on January 20, 2023, for usage as an adjunctive treatment alongside lifestyle changes and exercise in T2DM. Studies have shown that bexagliflozin can be used effectively (Table 2) [76-83] and safely, including patients with stage 3a and 3b chronic kidney disease [76].

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Table 2. Effectiveness of Bexagliflozin in Reducing HbA1c, Body Weight, and Systolic Blood Pressure

Remogliflozin is a SGLT2 inhibitor that was introduced in India in 2019 as a antidiabetic agent [84]. Additionally, it has been found to be useful in treating non-alcoholic steatohepatitis (NASH). A meta-analysis (Dutta et al [85]) of 535 subjects from three randomized clinical trials demonstrated that remogliflozin is as effective as pioglitazone and dapagliflozin (Table 3) [85-87], with similar rates of adverse effects. In contrast, the use of remogliflozin was associated with a greater reduction in weight, with a mean difference of -2.79kg (95% CI: -2.51 to -3.07 kg). Two studies were conducted to investigate the safety and tolerability of remogliflozin at doses of 500 mg and 750 mg twice a day (bis in die (BID)), which is higher than the typical dose of 100 mg BID. Both studies also included metformin at a daily dose of 2,000 mg. The results confirmed the safety and efficacy of this regimen [88, 89].

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Table 3. The Effectiveness of Remogliflozin in Reducing HbA1c, Body Weight, and/or Systolic Blood Pressure

However, another study suggested a potential link between remogliflozin therapy and cases of acute kidney injury [90].

Canagliflozin is the first approved SGLT2 inhibitor in the USA [91, 92]. It is indicated for the treatment of T2DM in combination with exercise and diet. It is known to reduce the risk of major cardiac events, end-stage renal disease and hospitalization for heart failure in patients with T2DM and chronic kidney disease. The CREDENCE trial aimed to assess the impact of canagliflozin on renal outcomes, including nephropathy in T2DM. The primary outcome was to evaluate the risk of end-stage renal disease, doubling of serum creatinine, or death from renal or cardiovascular causes. The group treated with 100 mg canagliflozin daily showed a significant risk reduction compared to the placebo group (hazard ratio (HR): 0.70; 95% CI: 0.59 to 0.82; P < 0.00001). The study also found a 32% risk reduction of end-stage renal disease (HR: 0.68; 95% CI: 0.54 to 0.86; P = 0.002). Similar observations were made for the risk of death from cardiovascular causes, myocardial infarction or stroke (HR: 0.80; 95% CI: 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (HR: 0.61; 95% CI: 0.47 to 0.80; P < 0.001) [93].

The CANVAS trial also demonstrated favorable results for canagliflozin, with a reduction in the combined risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (HR: 0.86; 95% CI: 0.75 to 0.97; P < 0.001 for noninferiority; P = 0.02 for superiority) in the canagliflozin group compared to the placebo group. Furthermore, canagliflozin caused HbA1c change by -0.58% (95% CI: -0.61% to -0.56%), body weight by -1.60 kg (95% CI: -1.70 kg to -1.51 kg) and systolic blood pressure by -3.93 mm Hg (95% CI: -4.30 to -3.56 mm Hg) [94].

The following table summarizes the reductions in HbA1c, weight, and/or systolic blood pressure obtained in other canagliflozin trials (Table 4) [93, 95-100].

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Table 4. Effectiveness of Canagliflozin in Reducing HbA1c, Body Weight and/or Systolic Blood Pressure

Empagliflozin is an oral SGLT2 inhibitor that gained approval in the USA in 2014. It has the highest selectivity to SGLT2 among flozins, more than 2,500-fold over SGLT1 [101]. Numerous studies have demonstrated the high efficacy of empagliflozin in reducing HbA1c, body weight, and systolic blood pressure (Table 5) [102-107]. Like canagliflozin, empagliflozin is also used to treat heart failure, in addition to treating T2DM.

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Table 5. The Effectiveness of Empagliflozin in Reducing HbA1c, Body Weight and SBP

The EMPA-REG OUTCOME trial confirmed the efficacy of empagliflozin in treating heart failure. The primary outcome of the study was to evaluate the composite risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in a group of patients treated with empagliflozin at doses of 10 mg or 25 mg compared with placebo; a 14% risk reduction was observed in the empagliflozin-treated groups (HR: 0.86; 95% CI: 0.74 to 0.99; P = 0.04 for superiority) [108].

Dapagliflozin was approved by the EMA in 2012, making it the first SGLT2 inhibitor to receive regulatory approval anywhere. Its primary indication is the treatment of T2DM alongside with diet and exercise. Dapagliflozin was proven to reduce the risk of hospitalization for heart failure and chronic kidney disease [33, 109, 110].

The DAPA-CKD trial involved 2,152 participants and its primary outcome was defined as a sustained decline in glomerular filtration rate (GFR) by at least 50%, end-stage renal disease, or death from renal or cardiovascular causes. The results showed a significant risk reduction by 44% (HR: 0.56; 95% CI: 0.45 to 0.68; P < 0.001). The study also revealed reduced risk of death from cardiovascular causes or hospitalization for heart failure (HR: 0.71; 95% CI: 0.55 to 0.92; P = 0.009) [111]. Furthermore, other studies also support the effectiveness of dapagliflozin in reducing HbA1c levels, body weight, and systolic blood pressure (Table 6) [63, 112-116].

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Table 6. The Effectiveness of Dapagliflozin in Reducing HbA1c, Body Weight, and Systolic Blood Pressure

All the studies presented in this review demonstrate the high efficacy of SGLT2 inhibitors in decreasing not only HbA1c, but also body weight and systolic blood pressure. These SGLT 2 inhibitors have beneficial effects on reducing cardiovascular risk and progression of chronic kidney disease. This outcome is not limited to relieving glucotoxicity on the vascular endothelium by reducing glycemia. Flozins also prevent glomerular hyperfiltration and damage, thus exerting their nephroprotective effect. Indirect inhibition of the renin-angiotensin-aldosterone system explains the cardioprotective activity of this group of drugs.

The most common adverse effect of SGLT2 inhibitors is an increased risk of urogenital infections due to glucosuria and osmotic diuresis. Euglycemic ketoacidosis or acute kidney injury are much less common and have only been reported in a few cases, such as with remogliflozin. However, numerous publications have demonstrated the safety of SGLT2 inhibitors.

Type 2 diabetes is often associated with weight gain and hypertension, therefore SGLT2 inhibitors should be one of the first-line agents in the treatment of this disease, especially in patients with comorbidities such as heart failure or kidney disease.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

Mateusz Nieczyporuk: conceptualization, design, methodology, analysis, writing, investigation and project. Pawel Tyrna: writing, editing, revision, graphics. Tomasz Cader, Aleksandra Sikora and Szymon Staneta: supervision, review, writing and editing. Each author read and approved the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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