SGLT2 Inhibition: A Novel Prospective Strategy in Treatment of Diabetes Mellitus

Abstract

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.

• type 2 diabetes
• kidney
• hyperglycemia
• sodium glucose co-transport
• sodium glucose co-transporter 2 (SGLT2) inhibitors

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with considerable morbidity and mortality.^1,2 Many epidemiological studies have demonstrated that hyperglycemia is the major risk factor for microvascular complications.^3,4 Hyperglycemia not only represents the biochemical marker for diagnosis of diabetes but also plays a critical role in the pathogenesis of insulin resistance and β-cell failure, that is, gluco-toxicity⁵ of T2DM. Thus, enhanced glycemic control in diabetes reduces the risk of microvascular complications as well as ameliorates the metabolic abnormalities contributing to the progressive course of the disease making tight glycemic control as the cornerstone of management in subjects with T2DM.⁶

Lifestyle changes such as healthy diet, weight loss, and increased physical activity improves glycemic control and cardiovascular risk factors in patients with type 2 diabetes.⁷ However, difficulty in maintaining weight loss and physical activity and their favorable effects over the long term necessitates pharmacotherapy in maintaining glycemic goals.⁸ Numerous treatment options are available with a variety of mechanisms of action for type 2 diabetes (e.g., insulin, sulfonylureas, meglitinides, biguanides, α-glycosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, amylin analogs, a dopamine agonist, and a bile acid sequestrant)^9,10; however, the proportion of patients achieving glycemic goals is incongruously low. Lack of treatment initiation and escalation, patient non-adherence, hypoglycemic risk with existing antidiabetic drugs, and progressive decline in β-cell function can all contribute to failure in the achievement of glycemic goals.^11,12 Therefore, new pharmacological therapies with novel mechanisms independent of insulin secretion or action and having a low predisposition to cause hypoglycemic risk may enhance patients’ ability to achieve glycemic control.¹³

GLUCOSE TRANSPORT IN THE KIDNEY

More than 99% of this glucose is re-absorbed by the proximal tubule, with <0.5 g/day excreted in the urine of healthy adults.¹⁴ Thus under normal conditions, ∼180 g of glucose is filtered by the kidney each day.^14,15 Glucose re-absorption from the glomerular filtrate is mediated by sodium glucose co-transporters (SGLTs), and thus re-absorption of glucose is dependent on the function of specific transporters. These transporters rely on the established inwardly directed electrochemical sodium gradient and is maintained by the sodium-potassium adenosine triphosphatase (ATPase) located on the basolateral membrane as the driving force for glucose entry into the cell. Once taken up into the proximal convoluted tubule cell via SGLT2, glucose exits the basolateral membrane into the interstitium by facilitative glucose transporters (GLUTs), primarily GLUT2 and, to a lesser extent, GLUT1.^16,17 Glucose then re-enters the circulation via peritubular capillaries. In normal subjects, the kidneys can maximally re-absorb ∼350–375 mg/min of glucose.^14,18 In hyperglycemic individuals, the transport maximum can be exceeded, and large amounts of glucose may be excreted into the urine.^13,19

FILTRATION AND RE-ABSORPTION OF GLUCOSE BY THE KIDNEY

Approximately 180 L of plasma, which contain ∼162 g of glucose, is filtered by the glomeruli every day. In normal subjects, virtually all of this glucose is completely re-absorbed in the proximal tubule with maximum glucose transport capacity (Tm) of ∼375 mg/min. In S1 and S3 segments of the proximal tubule, glucose transport is mediated by SGLTs. Active sodium transport generates sodium electrochemical gradient and provides the energy required for glucose transport. SGLT1 mediates glucose transport in the S3 segment and SGLT2 in the S1 segment. The filtered glucose load is always less than 375 mg/min in non-diabetic subjects, and thus all of the filtered glucose is re-absorbed and returned to the circulation. In type 2 diabetes subjects, the filtered glucose load exceeds 375 mg/min, and thus all of the glucose exceeding Tm is excreted in the urine.²⁰ Normal-glucose-tolerant subjects have a Tm for glucose above the filtered glucose load exhibiting major survival benefits, as it allows the kidneys to conserve this significant energy source for the brain. However, in diabetic patients this adaptive mechanism becomes maladaptive. Thus in the presence of hyperglycemia, it would be enviable for the kidney to excrete the excess filtered glucose load to restore normoglycemia. However, diabetic kidney having an increased Tm for glucose minimizes glucosuria and exacerbates hyperglycemia. When viewed in these stipulations, it is now apparent that the kidney contributes to the development and maintenance of hyperglycemia in individuals with diabetes. Moreover, increased glucose uptake in the proximal tubules in diabetics is also accompanied by increased sodium re-absorption, leading to extracellular volume expansion and thus an elevated blood pressure. Based on these pathophysiologic dysfunctioning, it pursues that development of inhibitors of the renal SGLT transporter may provide a rational and novel therapeutic strategy for the treatment of diabetic patients.^21,22

Two sodium-coupled GLUTs, SGLT1, and SGLT2, play an important role in the apical membrane of proximal tubular cells in the kidney. These transporters first bind Na⁺, and the electrochemical Na⁺ gradient generated by the Na⁺/K⁺-ATPase acts as the driving force for the symporter activity in glucose transport. SGLT1 is primarily expressed in enterocytes,²³ the function of which is to mediate active glucose and galactose transport across the apical membrane at low sugar concentration and mediating expression of facilitative transporters at high glucose concentration. In addition to the intestine and kidney, SGLT1 is also expressed in the brain and the heart. SGLT2 expression occurs predominantly in the luminal brush border of the proximal tubule of the renal cortex, where it acts as the principal transporter that mediates glucose resorption.²⁴ It is expressed to a much lower degree in other organs, including the liver. SGLTs are multifunctional proteins, and products of SLC5 genes that are predicted to exist in the human genome.^25,26 The specificity for SGLT2 over SGLT1 transporters, avoids impaired intestinal glucose absorption and diarrhea.²²

REGULATION OF SGLT2 EXPRESSION AND ACTIVITY IN DIABETES

There are previous data that have shown that a significant increase in the renal transport maximum for glucose was observed in type 1 diabetics,²⁷ and several rodent models of diabetes have shown upregulated GLUT2 protein in the renal proximal tubules of diabetic animals, sustaining the want for higher glucose efflux and glucose re-absorption.^28,29 Studies with renal proximal cells isolated from the urine of patients with type 2 diabetes have displayed an elevation of SGLT2 mRNA compared with healthy individuals³⁰ and in a rat model of diabetes, SGLT2 and hepatocyte nuclear factor 1α (HNF1α) mRNA expression was also increased yet reversed upon treatment with insulin or phlorizin, an inhibitor of SGLTs.³¹ Comparable changes have also been reported for GLUT2 in diabetic rats at day 6 of treatment with either insulin or phlorizin.³² HNF1α, which is a transcriptional activator encoded by the TCF1 gene, has been found to be mutated in maturity-onset diabetes of the young type 3 (MODY3).³³ Moreover, HNF1α^_/^_ homozygous mice, compared with wild-type or heterozygous healthy littermates, have shown to display deficient insulin secretion and hyperglycemia³⁴; however, plasma glucose concentrations were lower than expected in light of the severity of the insulin secretory defect, secondary to the associated glucose resorption defect in these mice.³⁵ Therefore, plasma glucose concentration seems to be an important modulator of SGLT2 activity which in part is regulated by HNF1α expression.²⁶

HYPERGLYCEMIA AND RENAL GLUCOSE RE-ABSORPTION

Studies in experimental animal models of diabetes^36,37 consistently have reported an increased rate of glucose re-absorption in the proximal tubule in uncontrolled diabetes. The molecular mechanism accountable for increased renal glucose re-absorption during hyperglycemia involves an augmented expression of GLUT genes in the proximal tubule. Thus, increased SGLT2 gene expression has been reported in renal proximal tubular cells in experimental animals³¹ and humans.³⁰ Several compelling studies have reported an increase in GLUT2 gene expression as well in the kidney in models of spontaneous diabetes, that is, the Zucker diabetic rat²⁹ and in streptozotocin-induced diabetes. Furthermore, treatment of hyperglycemia with insulin or phlorizin in experimental diabetic animal models has also shown to reverse the increase in SGLT2 gene expression caused by hyperglycemia³¹ as both insulin and phlorizin (which have very different effects on the plasma insulin and urinary glucose concentrations) prevented the increase in SGLT2 gene expression, thus making it likely that the elevated plasma glucose concentration provides the stimulus that ultimately leads to increased SGLT2 and GLUT2 mRNA/protein expression by the renal proximal tubular cells. Moreover, in both T2DM and T1DM patients, the renal Tm for glucose has also been shown to be elevated. The study by Farber et al.³⁸ has shown that correction of hyperglycemia resulted in a decrease in Tm for glucose and the appearance of glucosuria. Thus, almost 50 years ago investigators already had established an increase in the renal Tm for glucose in response to chronic hyperglycemia.⁶

OXIDATIVE STRESS AND GLUCOSE

One of the corollaries of excessive intracellular glucose levels under hyperglycemic conditions is an increased rate of oxidative phosphorylation, as well as an increase in the metabolism of glucose to sorbitol by aldose reductase. In addition, hyperglycemia also results in the activation of NADPH oxidase, thus augmenting the production of superoxide anion and hydrogen peroxide (H₂O₂). In a recent study the investigators examined the mechanisms responsible for the H₂O₂ production that occurred as the consequence of hyperglycemia in addition to the effect of H₂O₂ on the activity of the Na⁺/glucose co-transport system (SGLT) in primary cultures of renal proximal tubule cells (PTCs). The result of the study demonstrated that when primary PTCs were cultured in the presence of high glucose, the Na⁺/glucose co-transport system was inhibited, indicated by uptake studies utilizing α-methyl-D-glucoside (α-MG), a non-metabolizable analog of D-glucose. Pretreatment of the cultures with aminoguanidine or pyridoxamine (inhibitors of the accumulation of advanced glycation end products), rotenone (an inhibitor of the mitochondrial electron transport chain), or apocynin or diphenylene iodonium (inhibitors of NADPH oxidase) locked the observed changes that occurred as a consequence of the incubation of the PTCs with high glucose. An increase in H₂O₂ levels, as well as lipid peroxide production, and a decrease in the activity of both catalase and the level of glutathione (GSH) endogenous antioxidants were also observed. The high glucose-induced decrease in the level of the Na⁺/glucose co-transporter was significantly prohibited by aminoguanidine, rotenone, or apocynin. Thus, high glucose exerted an inhibitory effect on the level of the Na⁺/glucose co-transport system and the activity of the Na⁺/glucose co-transport system, in part, due to the effects of H₂O₂, the consequent formation of advanced glycation end products (AGEs), the increase in mitochondrial metabolism, and in NADPH oxidase activity in the PTCs. These compelling evidences have also showered light on the involvement of oxidative stress in the upregulation of SGLTs.³⁹

RATIONALE FOR SGLT2 INHIBITION

There are a number of SGLT2 inhibitors in various stages of clinical development for the treatment of diabetes. SGLT2 inhibitors hinder the function of SGLT2 in proximal convoluted tubules of kidney and induce glycosuria. Animal studies and clinical trials have discovered that SGLT2 inhibition lowers plasma glucose levels, decreases gluco-toxicity, and reduces plasma insulin and glycosylated hemoglobin levels, exerting beneficial effects in the diabetic state.^40,41 The reduction in the plasma glucose level improves liver sensitivity to insulin, which further suppresses hepatic glucose production (HGP), leading to an improvement in the diabetic state.⁴² Moreover, by causing glycosuria, SGLT2 inhibitors not only reduce plasma glucose levels but also cause a net loss of calories from the body and thus maintain overall negative energy balance, which results in a reduction in adiposity and weight loss. SGLT2 inhibitors also exhibit blood pressure-lowering effect owing to their mild diuretic and weight-reducing actions.^43,44 As compared to currently available antidiabetic drugs, SGLT2 inhibitors do not stimulate insulin secretion, neither do they pose the risk of hypoglycemia nor cause gastrointestinal side effects. The novel mechanism of action recommends their possible use in combination with other antidiabetic agents so as to exert additive or synergistic effects in lowering glucose levels in T2DM. However, the efficacy of SGLT2 inhibitors is dependent on the amount of glucose filtered through the glomeruli, as the glomerular filtration rate declines in renal impairment, and the efficacy of the SGLT2 inhibitors also decreases. Renal dysfunction is a common complication of T2DM, with 35.2% of patients having moderate to end-stage renal impairment,⁴⁵ which probably limits the therapeutic efficacy of SGLT2 inhibitors to diabetic patients with normal renal function or with mild renal impairment at best. There is also a need to monitor renal function prior to giving this drug and during the course of therapy. The drug might also undergo a therapeutic failure with progressive deterioration of renal function during the course of treatment.⁴⁶

The effects are independent of insulin secretion or action, thus making them effective during the later stages of the disease when insulin secretagogues and insulin sensitizers have lost their efficacy because of the progressive decline in β-cell function. In addition, there is a decreased risk of major hypoglycemia events as the actions of SGLT2 inhibitors are independent of insulin. Moreover, by increasing the excretion of glucose, SGLT2 inhibitors may promote weight loss, thus ameliorating the pathophysiology of type 2 diabetes related weight gain. The result of studies in diabetic rat models demonstrated that phlorizin-promoted glucose excretion, normalizing plasma glucose levels and reversed insulin resistance.^42,47 Moreover, a number of selective SGLT2 inhibitors have been synthesized to deal with the limitations of phlorizin. Preclinical data are existing for remogliflozin, sergliflozin, and dapagliflozin, which caused dose-dependent increases in renal glucose excretion in a number of species with decrease in plasma glucose without increasing insulin secretion in diabetic rat models.⁴⁸

CLINICAL APPLICATIONS OF SGLT2 INHIBITORS

SGLT2 inhibitors would have the benefit of lowering plasma glucose levels irrespective of the underlying pathogenesis of hyperglycemia. Certainly, these drugs may be useful in both type 1 and type 2 diabetes induced “glucose toxicity” where high glucose levels per se can directly inhibit β-cell function. As these drugs do not affect glucose metabolism, SGLT2 inhibitors could be combined easily with other oral and injectable treatments for diabetes. Additionally, SGLT2 inhibitors may have therapeutic effects on other mechanisms of the metabolic syndrome, for example, lipids, hypertension, and obesity. Sergliflozin indicated a weight loss effect in preliminary data, which is being tested in larger trials in obese patients where increased calorie loss in the urine will simply lead to a compensatory increase in feeding. However, it is also expected that SGLT2 inhibition will emulate the metabolic effects of carbohydrate restriction by increasing cellular utilization of other fuel sources for energy production.⁴⁹ Regarding the issues of safety and tolerability, evidence for the safety of renal glycosuria on long-term kidney function comes from individuals with familial renal glycosuria. However, it is vague whether augmented urinary glucose concentrations will increase the risk of urinary tract infection (UTI). A prospective study has shown that more than 600 women with diabetes showed no increase in the risk of developing UTI due to glycosuria.⁵⁰ These data are supported by phase I and II clinical trials with SGLT2 inhibitors that showed no significant difference in UTIs among patients receiving active therapy compared with placebo. However, as the blood–brain barrier does not employ sodium–glucose symporters under normal conditions, the subsistence of a new type of SGLT-like transporter cannot be excluded. However, rodent studies have shown that phlorizin enhances memory, facilitates learning, and counteracts the effects of insulin to impair memory retention. Therefore, SGLT2 specificity is important for new agents entering clinical development.⁵¹

SGLT2 INHIBITION IN TREATMENT OF DIABETES MELLITUS

Some SGLT2 inhibitors are now in clinical trials, and published data are available for dapagliflozin, which is having 1200-fold more selectivity for SGLT2 than SGLT1. A study where dapagliflozin was administered for 14 days to drug-naive or metformin-treated patients with type 2 diabetes, and it induced a dosage-dependent increase in urinary glucose excretion, reaching a maximum of 70 g/days, and improved fasting blood glucose and glucose tolerance.⁵² In a more protracted study, a total of 348 drug-naive patients with type 2 diabetes randomly assigned to receive 2.5, 5.0, 10.0, 20.0, or 50.0 mg of dapagliflozin, 1.5 g of metformin, or placebo⁵³ showed a significant reduction in glycosylated hemoglobin, fasting plasma glucose, and body weight by the end of the study. Hypoglycemic episodes were analogous when compared with the metformin-treated group, with a high incidence of genital infections. Both studies with dapagliflozin reported incomplete inhibition of SGLT2 with lower levels of glucosuria than in the most severe forms of FRG. Moreover, it is possible that the accumulating tubular glucose competes with dapagliflozin for SGLT2 binding, thus limiting the degree of inhibition. Inhibition of SGLT2 is probably safe and free of undue consequences for patients from chronic glucosuria, which can be deduced from the observation of patients who have FRG and in whom naturally occurring mutations of SGLT2 manifest as a mostly benign disorder.²⁶

METABOLIC EFFECTS OF SGLT2 INHIBITORS ON GLUCOSE METABOLISM

Normal Animals

Pharmacological inhibition of the SGLT2 transporter in normal animals resulted in significant glucosuria with minimal or no change in the fasting plasma glucose concentration. Single-dose administration of three SGLT2 inhibitors, T-1095,⁵⁴ sergliflozin,⁵⁵ and dapagliflozin,⁴¹ caused a transient (up to 6 h) decrease in plasma glucose concentration when administered to fasted normal rats; no significant change in the fasting plasma glucose concentration was observed 24 h after drug administration. Chronic treatment (>6 weeks) of normal animals with SGLT2 inhibitors had no significant effect on the plasma glucose concentration despite marked dose-dependent glucosuria. No significant effect of SGLT2 inhibition on the fasting plasma glucose concentration in normal animals, despite significant glucosuria, indicates activation of counter-regulatory mechanisms that increase endogenous HGP to precisely compensate for the increased urinary glucose loss because of the inhibition of renal glucose re-absorption. Studies with phlorizin in normal dogs have reported that the glucosuria was associated with a marked increase in HGP and no significant change in arterial plasma glucose concentration.⁵⁶ Consistent with the supposition, administration of the SGLT2 inhibitor, T-1095, in normal animals showed a decrease in fasting plasma insulin concentration. In disparity to the insignificant effect of SGLT2 inhibitors on the fasting plasma glucose concentration in normal rats, a single dose of an SGLT2 inhibitor given 30 min before an oral glucose load reduced the area under the plasma glucose concentration curve by 50%. The same effect on postprandial plasma glucose concentration has been observed with all three SGLT2 inhibitors as well. However, no significant change in the area under the plasma glucose curve after glucose ingestion was observed during chronic SGLT2 inhibitor treatment.

Diabetic Animals

In diabetic animals, SGLT2 inhibitors have a very diverse effect on glucose metabolism as compared with non-diabetic animals. In streptozotocin-induced diabetic rats, a single oral dose (100 mg/kg) of T-1095 has shown to reduce the fasting plasma glucose concentration from approximately 18 mM to less than 5.5 mM.⁵⁷ Correspondingly, a single oral dose of dapagliflozin has shown to reduce the fasting plasma glucose concentration in Zucker diabetic rats in a dose-dependent fashion, and the maximally effective dose (1 mg/kg) decreases the plasma glucose concentration from approximately 20 mM to approximately 5.5 mM.⁴¹ Moreover, the decrease in plasma glucose concentration was also accompanied by an increase in fasting plasma insulin concentration, which may be involved in decrement of HGP. Furthermore, plasma free fatty acid (FFA), which also was elevated in the diabetic rats, was normalized with T-1095 treatment. Because elevated plasma FFA levels stimulate hepatic gluco-neogenesis and cause hepatic insulin resistance, normalization of the fasting plasma FFA concentration also could have contributed to the decline in basal HGP. Chronic hyperglycemia augments HGP by stimulating glucose-6-phosphatase, the rate-limiting enzyme for glucose exit from the hepatocyte, that is, gluco-toxicity. Chronic hyperglycemia in T2DM subjects augments glucose uptake in muscle by mass action effect. Because both glucose oxidation and glycogen synthesis are markedly impaired in diabetic muscle, the glucose that is taken up in increased amounts during the basal post-absorptive state is released as lactate, which is returned to the liver where it stimulates hepatic gluco-neogenesis, that is, acceleration of the Cori cycle. Correction of the hyperglycemia, by reducing lactate production in muscle and adipocytes, would make less lactate available to the liver for gluco-neogenesis.

Insulin Resistance

Hyperglycemia by itself exacerbates insulin resistance as well as β-cell dysfunction referred to collectively as gluco-toxicity. Chronic hyperglycemia in partially (90%) pancreatectomized diabetic rat resulted in the development of severe insulin resistance in skeletal muscle and liver, which essentially provides an animal model for insulin-deficient T2DM.^42,47 In vivo measurement of whole body insulin-stimulated glucose disposal by using insulin clamp showed an increase in association with enhanced insulin-stimulated glucose uptake in skeletal muscle in vitro. Moreover, correction of hyperglycemia in streptozotocin-treated animals with T-1095 decreased HGP to near normal values, indicating improved hepatic insulin resistance.⁵⁷ In Zucker diabetic rats, dapagliflozin has also shown augmentation in insulin-stimulated hepatic glucose disposal as well as suppression of HGP by insulin. Captivatingly, this 2-week study with dapagliflozin neither enhanced insulin-stimulated glucose uptake in skeletal muscle or white adipocytes nor inhibited facilitative glucose transport in human adipocytes.⁴¹ Furthermore, in streptozotocin-treated rats, normalization of insulin-stimulated glucose disposal and suppression of HGP with T-1095 were associated with an improvement in insulin signaling in skeletal muscle and liver. In the liver, T-1095 treatment increased insulin receptor, insulin receptor substrate-1 and -2 tyrosine phosphorylation, and insulin-stimulated phosphatidylinositol-3 kinase activity. Taken together, the results described above emphasizes the lethal effect of hyperglycemia on insulin resistance in liver and muscle and exhibits that although the primary mechanism of action of the SGLT2 inhibitors is to inhibit glucose re-absorption by the kidney by correcting hyperglycemia, they also ameliorate the muscle and hepatic insulin resistance.

β-Cell Function

Persistently elevated plasma glucose levels inhibit insulin secretion in vivo in humans and animals and in vitro in cell culture systems.^58,59 Moreover, improvement in hyperglycemia with intensive insulin therapy improves insulin secretion in human T2DM subjects. However, in normal animals, a small (16 mg/dL) augmentation in mean day-long plasma glucose concentration has shown to reduce both first- and second-phase insulin secretion by 50%.⁵⁸ The response of plasma insulin to treatment with an SGLT2 inhibitor depends on the glucose tolerance status of the animal as well. Chronic (12 weeks) treatment with T-1095 in normal animals has shown to cause a small non-significant decrease in fasting plasma insulin concentration and insulin response during the oral glucose tolerance test (OGTT).⁶⁰ On the contrary, T-1095 has shown to be significantly increased in both the fasting plasma insulin concentration and the plasma insulin response during the OGTT in diabetic animals.⁵⁴ Furthermore, increased insulin response during the OGTT documents a vigorous improvement in β-cell function after restoration of normoglycemia with T1095. Moreover, treatment (8 weeks) with T-1095 in Goto-Kakizaki diabetic rats enhanced first-phase insulin secretion by approximately 30%, measured with the perfused pancreas technique. Thus, all of these studies are quite consistent and highlight the essentiality of the role of gluco-toxicity in the development of β-cell failure in T2DM. They also demonstrate that correction of the elevated blood glucose levels with a SGLT2 inhibitor has a favorable effect on β-cell function.⁶

FUTURE DIRECTIONS AND CONCLUDING REMARKS

Current information from experimental animals as well as human signifies inhibition of the SGLT2 transporter as an effective and novel strategy to control the plasma glucose concentration in type 2 diabetes subjects. In addition to a good safety profile, SGLT2 inhibitors can be used in combination with all other antidiabetic medications with anticipated additive efficacy on glycemic control. Clinical trials of various SGLT2 inhibitors are in the early stages; nonetheless, data from investigations so far are hopeful. Moreover, SGLT2 inhibition represents a particularly appealing approach to treating diabetes since SGLT2 inhibitors do not directly influence insulin secretion, thereby utilizing a novel mechanism of action. This novel mechanism of action suggests that SGLT2 inhibitors might have the prospective to be used in combination with oral antidiabetic agents as well as insulin to exert additive or synergistic effects on lowering glucose levels in T2DM. However, further studies in large numbers of human subjects as well as long-term safety data are necessary to define efficacy, safety, and how to most effectively use these agents in the treatment of diabetes.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.