The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear.

This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms.

On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥ 0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of heart failure hospitalizations and mortality (P-interaction = .467). However, decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805).

Acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes.

NCT03505788.

One class of oral medicines used in the management of type 2 diabetes is sodium glucose co-transporter 2 (SGLT2) inhibitors. Their mode of action is unique and is not dependent on beta-cell function or the degree of a person's insulin resistance. This article reviews the use of SGLT2 inhibitors in managing type 2 diabetes, explaining the potential benefits and side effects of these medicines. It also explains the role of healthcare professionals, including nurses, in ensuring these medicines are used safely and appropriately.

We review a collection of published renal epithelial transport models, from which we build a consistent and reusable mathematical model able to reproduce many observations and predictions from the literature. The flexible modular model we present here can be adapted to specific configurations of epithelial transport, and in this work we focus on transport in the proximal convoluted tubule of the renal nephron. Our mathematical model of the epithelial proximal convoluted tubule describes the cellular and subcellular mechanisms of the transporters, intracellular buffering, solute fluxes, and other processes. We provide free and open access to the Python implementation to ensure our multiscale proximal tubule model is accessible; enabling the reader to explore the model through setting their own simulations, reproducibility tests, and sensitivity analyses.

Sodium-glucose cotransporter 2 inhibitors are a novel class of anti-hyperglycemic agents. Although several cases of perioperative euglycemic diabetic ketoacidosis have been linked to these medications, the association remains unclear. This study aimed to examine the association between sodium-glucose cotransporter 2 inhibitor use and the incidence of perioperative metabolic acidosis with euglycemia, the surrogating outcome of perioperative euglycemic diabetic ketoacidosis.

This was a retrospective, matched cohort study, which was conducted in the intensive care unit of a tertiary care facility in Japan. We identified patients aged 20 years or older with diabetes mellitus who received pharmacologic therapy and were admitted to the intensive care unit after elective surgery between April 2014 and March 2019. We extracted the following data from the electronic medical record for matching: age, sex, surgery year, surgical site, hemoglobin A1c level, and prescription for sodium-glucose cotransporter 2 inhibitors. Eligible patients were divided into two groups, those who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2-i group) and those who were not (control group). For each patient in the SGLT2-i group, we randomly selected four patients from the control group matched for the extracted characteristics. The primary outcome was the incidence of metabolic acidosis with an elevated anion gap and euglycemia. The secondary outcome was the lowest pH value of each patient during their ICU stay.

A total of 155 patients were included in this study. Patients receiving sodium-glucose cotransporter 2 inhibitors had comparable characteristics to control participants; however, the proportions of patients undergoing dialysis were not similar. Metabolic acidosis with euglycemia was seen in 7/31 (22.6%) patients receiving sodium-glucose cotransporter 2 inhibitors and in 10/124 (8.1%) control patients (p = 0.047).

This study shows that the use of sodium-glucose cotransporter 2 inhibitors is associated with a significantly higher incidence of metabolic acidosis with euglycemia. Patients receiving sodium-glucose cotransporter 2 inhibitors who are scheduled to undergo invasive surgical procedures should be closely monitored for the development of euglycemic diabetic ketoacidosis.

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

In the kidney glucose is freely filtered by the glomerulus and, mainly, reabsorbed by sodium glucose cotransporter 2 (SGLT2) expressed in the early proximal tubule. Human proximal tubule epithelial cells (PTECs) undergo pathological and fibrotic changes seen in diabetic kidney disease (DKD) in response to elevated glucose. We developed a specific in vitro model of DKD using primary human PTECs with exposure to high D-glucose and TGF-β1 and propose a role for SGLT2 inhibition in regulating fibrosis.

Western blotting was performed to detect cellular and secreted proteins as well as phosphorylated intracellular signalling proteins. qPCR was used to detect CCN2 RNA. Gamma glutamyl transferase (GT) activity staining was performed to confirm PTEC phenotype. SGLT2 and ERK inhibition on high D-glucose, 25 mM, and TGF-β1, 0.75 ng/ml, treated cells was explored using dapagliflozin and U0126, respectively.

Only the combination of high D-glucose and TGF-β1 treatment significantly up-regulated CCN2 RNA and protein expression. This increase was significantly ameliorated by dapagliflozin. High D-glucose treatment raised phospho ERK which was also inhibited by dapagliflozin. TGF-β1 increased cellular phospho SSXS Smad3 serine 423 and 425, with and without high D-glucose. Glucose alone had no effect. Smad3 serine 204 phosphorylation was significantly raised by a combination of high D-glucose+TGF-β1; this rise was significantly reduced by both SGLT2 and MEK inhibition.

We show that high D-glucose and TGF-β1 are both required for CCN2 expression. This treatment also caused Smad3 linker region phosphorylation. Both outcomes were inhibited by dapagliflozin. We have identified a novel SGLT2 -ERK mediated promotion of TGF-β1/Smad3 signalling inducing a pro-fibrotic growth factor secretion. Our data evince support for substantial renoprotective benefits of SGLT2 inhibition in the diabetic kidney.

Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.

Sodium glucose co-transporter 2 (SGLT2) inhibitors are effective antihyperglycemic agents by inhibiting glucose reabsorption in the proximal tubule of the kidney. Besides improving glycemic control in patients with type 2 diabetes, they also have additional favorable effects, such as lowering body weight and body fat. Several clinical studies have demonstrated their positive effect in reducing cardiovascular morbidity and mortality. Furthermore, the use of SGLT2 inhibitors were associated with fewer adverse renal outcomes comparing to other diabetic agents, substantiating their renoprotective effect in diabetic patients. SGLT2 inhibitors have also remarkable effect on lipid metabolism acting at different cellular levels. By decreasing the lipid accumulation, visceral and subcutaneous fat, they do not only decrease the body weight but also change body composition. They also regulate key molecules in lipid synthesis and transportation, and they affect the oxidation of fatty acids. Notably, they shift substrate utilization from carbohydrates to lipids and ketone bodies. In this review we intended to summarize the role of SGLT2 inhibitors in lipid metabolism especially on lipoprotein levels, lipid regulation, fat storage and substrate utilization.

Upregulation of the sodium glucose co-transporter (SGLT2) is implicated in acute renal injury (ARI) progression and is regulated by extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) or prostaglandin E2 (PGE2). This study aimed to assess the possible protective effect of nebivolol on renal ischemia/reperfusion (IR) and glycerol-induced ARI targeting SGLT2 via modulating the ERK-HIF1α pathway.

Rats were divided into control, sham, IR or nebivolol-treated group, in which rats were treated with nebivolol (10 mg/kg) for 3 days prior to the induction of IR. The rats were subjected to renal ischemia by bilateral clamping of the pedicles for 45 min, followed by 24 h reperfusion. Another group of rats received the vehicle or nebivolol (10 mg/kg) for 3 days followed by injection of 50% glycerol (8 ml/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers [malondialdehyde (MDA) and NADPH oxidase] and kidney levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 were determined. Additionally, renal sections were used for histological grading of renal injury and immunological expression of SGLT2.

ARI rats showed significantly increased SBP, poor kidney function tests, increased oxidative stress, iNOS, NO, HIF1α levels, decreased PGE2 and ERK phosphorylation and upregulation of SGLT2 expression. Nebivolol treatment protected against the kidney damage both on the biochemical and histological levels.

Nebivolol has a direct renoprotective effect, at least in part, by down-regulating SGLT2 possibly via modulating HIF1α, ERK activity and PGE2 production.

Sodium-glucose cotransporter type-2 inhibitors (SGLT2is) reduce glomerular hyperfiltration in diabetic people with early diabetic nephropathy. The objective of this report was to assess changes in glomerular filtration rate in healthy cats after treatment with a SGLT2i. Eight healthy research adult castrated male cats were used in a randomized, controlled, cross-over study design. We induced isolated renal tubular glucosuria by dosing cats with the SGLT2i dapagliflozin. The cats received by mouth 10 mg dapagliflozin or control every 24 h in each of the 4, 5-d trial periods that were separated by a 7-d washout period. We assessed glomerular filtration rate (iohexol clearance method), serum urea, creatinine, symmetric dimethylarginine, and 24-h sodium and chloride urinary excretion on the fifth day of each trial period. We analyzed the data with a mixed linear model that included the fixed effects of treatment (treated and control) and trial period, and the random effect of the cat. Compared with controls, cats treated with dapagliflozin had a significant increase in mean (±SE) glomerular filtration rate (3.1 ± 0.2 vs 2.5 ± 0.2 mL/kg/min; P = 0.01), whereas there were no significant differences in serum urea, creatinine and symmetric dimethylarginine, and 24-h urine sodium and chloride excretion. We propose that dapagliflozin-mediated delivery of sodium and glucose distal from the proximal convoluted tubule induced compensatory increased sodium absorption at the thick ascending loop of Henle that resulted in decreased sodium delivery to the distal tubule leading to tubuloglomerular feedback-mediated glomerular hyperfiltration. Future studies should determine if SGLT2is' renoprotective effect in people can be enhanced with the addition of a Na⁺-K⁺-Cl^- diuretic and whether dapagliflozin will be useful in mitigating proteinuria and hypertension that follow glomerular hyperfiltration in diabetic companion animals in a similar mechanism as in people.

Sodium-glucose cotransporter-2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol-induced ARI by determining its effect on SGLT2 via modifying ERK-HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined. Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up-regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down-regulating SGLT2.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.

Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, but the molecular mechanisms are still unknown. In clinical trials GLP-1 analogs exerted important impact on renal composite outcomes, primarily on macroalbuminuria, possibly through suppression of inflammation-related pathways, however enhancement of natriuresis and diuresis is also one of possible mechanisms of nephroprotection. Dapagliflozin, canagliflozin, and empagliflozin are SGLT2i drugs, useful in reducing hyperglycemia and in their potential renoprotective mechanisms, which include blood pressure control, body weight loss, intraglomerular pressure reduction, and a decrease in urinary proximal tubular injury biomarkers. In this review we have discussed the potential synergistic and/or additive effects of GLP 1 RA and SGLT2 inhibitors on the primary onset and progression of kidney disease, and the potential implications on current guidelines of diabetes type 2 management.

Breath analysis is used to detect the composition of exhaled gas. As a quick and non-invasive detection method, breath analysis provides deep insights into the progression of various kinds of diseases, especially those with metabolism disorders. Abundant information on volatile compounds in diabetic patients has been studied in numerous articles in the literature. However, exhaled gas in diabetic patients can be altered by various complications. So far, little attention has been paid to this alteration. In our paper, we found that under air pollution conditions, diabetic patients exhale more nitric oxide. Diabetic patients with heart failure exhale more acetone than those without heart failure. After ¹³C-labeled glucose intake, patients infected with Helicobacter pylori exhaled more ¹³C and less ¹⁸O than those without infection. Exhalation with chronic kidney disease changes volatile organic compounds on a large scale. Diabetic patients with ketoacidosis exhale more acetone than those without ketoacidosis. Some specific volatile organic compounds also emanate from diabetic feet. By monitoring breath frequency, diabetic patients with obstructive sleep apnea syndrome exhibit a unique breath pattern and rhythm as compared with other diabetic patients, and sleep apnea is prevalent among diabetic patients. In addition to clinical findings, we analyzed the underlying mechanisms at the levels of molecules, cells and whole bodies, and provided suggestions for further studies.

As shown in our previous paper (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017), mesangial matrix expansion in diabetic nephropathy (DN) results for a major part from the accumulation of worn-out undegraded glomerular basement membrane material. Here, based on the reevaluation of >900 biopsies of DN, we show that this process continues with the progression of the disease finally leading to the herniation of the matrix-overloaded tuft through the glomerular entrance to the outside. This leads to severe changes in the glomerular surroundings, including a dissociation of the juxtaglomerular apparatus with displacement of the macula densa. The herniation is associated with a prominent outgrowth of glomerular vessels from the tuft. Mostly, these aberrant vessels are an abnormal type of arteriole with frequent intramural insudations of plasma. They spread into glomerular surroundings extending in intertubular and periglomerular spaces. Their formation is associated with elevated mRNA levels of vascular endothelial growth factor-A, angiopoietins 1 and 2, and the corresponding receptors. Functionally, these processes seem to compromise tubuloglomerular feedback-related functions and may be one factor why Na⁺-glucose cotransporter-2 inhibitors are not effective in advanced stages of DN.

Conventional therapies to prevent type 2 diabetes mellitus (T2DM) complications are only partially effective. Therefore, new therapeutic approaches leading to additional risk reduction are required. While many anti-diabetic medications have been prescribed world-wide for controlling T2DM over the past half-century, sodium-glucose co-transporter-2 (SGLT2) inhibitors are relatively new. In addition to their plasma glucose lowering effect, SGLT2 inhibitors have been shown to reduce considerably cardiovascular mortality rate in patients with T2DM.

Since, a risk and benefit analysis of co-administration of SGLT2 inhibitors and other anti-diabetic agents in patients who suffer from hypertension, heart failure or renal deficiency is currently lacking, the main objective of this article is to review the recent literature and provide the health care professionals with evidence-based opinions on the subject.

SGLT2 inhibitors have relatively safe profiles and can efficiently decrease HbA1c as well as fasting and postprandial glucose levels. Furthermore, SGLT2 inhibitors administrations are not associated with significant hypoglycemic episodes or weight gain. Thus, combination of SGLT2 inhibitors and other less harmful anti-diabetic medicines could be considered if there is no any contraindication.

Diabetes mellitus prevalence is increasing worldwide leading to increased morbidity and mortality through diabetes related microvascular and macrovascular disease. The treatment of hypertension has been shown to be a major therapeutic intervention for the prevention of cardiovascular events and other diabetes related complications in diabetes. Sodium-glucose co-transporter inhibitors (SGLT2i) are newly introduced anti-diabetes drugs that lower blood glucose by the inhibition of glucose reuptake and the induction of glycosuria. However, there is increasing evidence showing their cardiovascular benefit beyond the improvement of glycemic control. Here we review the latest findings on the effect of SGLT2i on blood pressure in diabetes.

Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients.

This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.

RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

To review the role of the sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of type 2 diabetes (T2DM), including the effects on renal and cardiovascular (CV) outcomes.

A literature search of MEDLINE databases (1964 through May 2018) was conducted utilizing key words sodium-glucose co-transporter-2 inhibitors, SGLT2 inhibitors, and diabetes; additional limits for drug names were added.

Available English-language data from reviews, abstracts, presentations, and clinical trials of use of SGLT2 therapy specifically detailing outcomes on CV and renal disease in humans were reviewed.

This review will explore the role of the SGLT2 inhibitors on CV and renal outcomes in patients with T2DM. Relevance to Patient Care and Clinical Practice: A paradigm shift regarding the regulation of medications for the treatment of T2DM has resulted in the need for CV outcomes data as part of the drug approval process. Reduction of major CV events and progression of nephropathy in patients with T2DM represent major outcomes of clinical significance. Few medications have been able to establish a reduction in these end points; data for the use of SGLT2 inhibitors are favorable in this regard.

The SGLT2 inhibitors represents a class of medications that reduce glucose levels via a novel and complementary mechanism. Emerging evidence suggests a plausible explanation for the observed reduction in adverse renal and CV outcomes in recent clinical trials. Questions remain whether these agents reduce renal disease risk greater than achievement of the same glycemic goals as other antidiabetics and whether CV and renal benefits are reproducible in high-risk patients with chronic kidney disease.

SGLT2 inhibitors were promising and novel antidiabetic drugs which suppressed glucose reabsorption and increased urinary glucose exertion. This review paper are aimed to summarize the recent progress of SGLT2 inhibitors during the last 5 years. This paper first summarizes the information of SGLT2 inhibitors, including mechanism, evolution and then focuses on the recent efforts on structure-activity relationships and structural optimization of SGLT2 inhibitors. Finally, the corresponding clinical therapeutic efficacy and adverse drug reaction in patients with Type 2 diabetes are discussed in detail.

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 ) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.

A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2 ). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were -0.7% (-7.5 mmol/mol) and -0.8% (-8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%-14.1%) vs placebo (0%-1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups.

Ertugliflozin added to metformin and sitagliptin was well-tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.

We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%-10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks).

This was a double-blind, 26-week, multicentre study with ongoing 78-week extension (ClinicalTrials.gov identifier: NCT02033889). A total of 621 participants were randomized 1:1:1 to placebo, or ertugliflozin 5 or 15 mg/d. The primary endpoint was change from baseline at week 26 in HbA1c. Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP) and number of participants with HbA1c <7.0% (53 mmol/mol). Pre-specified adverse events (AEs) of special interest and percent change from baseline in bone mineral density (BMD) were also assessed at week 26.

At week 26, the placebo-adjusted least-squares mean change from baseline HbA1c (8.1%) was -0.7% and -0.9% for ertugliflozin 5 and 15 mg, respectively (both P < .001), to final means of 7.3% and 7.2%, respectively. The odds of HbA1c <7.0% were significantly greater in both ertugliflozin groups vs placebo. Ertugliflozin significantly reduced FPG, body weight, SBP and DBP vs placebo. The incidence of genital mycotic infections was higher in the ertugliflozin groups (female subjects: placebo, 0.9%; ertugliflozin 5 mg, 5.5%; ertugliflozin 15 mg, 6.3% [P = .032]; male subjects: 0%; 3.1%; 3.2%, respectively), as was the incidence of urinary tract infections and symptomatic hypoglycaemia. The incidence of hypovolaemia AEs was similar across groups. Ertugliflozin had no adverse impact on BMD at week 26.

Ertugliflozin added to metformin in patients with inadequately controlled T2DM improved glycaemic control, reduced body weight and BP, but increased the incidence of genital mycotic infections.

This study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.

This phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1c ≥ 7.0% and ≤ 9.0% on stable metformin ≥ 1500 mg/day 1:1:1 to ertugliflozin 15 or 5 mg once-daily (QD), or glimepiride (titrated from 1 mg QD). The primary hypothesis was that ertugliflozin 15 mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment difference < 0.3%).

Mean baseline HbA1c of randomized patients (N = 1326) was 7.8%. Mean and median doses of glimepiride were 3.0 mg/day throughout the study. At week 52, the least squares mean change (95% CI) from baseline in HbA1c was - 0.6% (- 0.7, - 0.5), - 0.6% (- 0.6, - 0.5), and - 0.7% (- 0.8, - 0.7) in the ertugliflozin 15 mg, ertugliflozin 5 mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15 mg and glimepiride of 0.1% (- 0.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups.

Ertugliflozin 15 mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride.

Clinicaltrials.gov NCT01999218.

Ertugliflozin is an oral sodium-glucose cotransporter 2 inhibitor that is being developed to treat type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of co-initiation of ertugliflozin and sitagliptin compared with placebo in patients with T2DM inadequately controlled on diet and exercise.

In this phase III, randomized, double-blind, multicenter, placebo-controlled 26-week study (NCT02226003), patients with T2DM and glycated hemoglobin (HbA1c) 8.0-10.5% on diet/exercise were randomized 1:1:1 to ertugliflozin 5 mg once daily (QD) and sitagliptin 100 mg QD (E5/S100), ertugliflozin 15 mg QD and sitagliptin 100 mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26.

The mean baseline HbA1c of the randomized patients (n = 291) was 8.9%. At week 26, both ertugliflozin/sitagliptin treatments provided significant reductions from baseline in HbA1c compared with placebo [least squares mean HbA1c change (95% confidence intervals) from baseline was - 0.4% (- 0.7, - 0.2), - 1.6% (- 1.8, - 1.4), and - 1.7% (- 1.9, - 1.5) for placebo, E5/S100, and E15/S100, respectively]. At week 26, 8.3%, 35.7%, and 31.3% of patients receiving placebo, E5/S100, and E15/S100, respectively, had HbA1c < 7.0%. Significant reductions in fasting plasma glucose, 2-h post-prandial glucose, body weight, and systolic blood pressure were observed with both ertugliflozin/sitagliptin groups compared with placebo. The incidence of adverse events (AEs) was similar across the groups. The incidences of the pre-specified AEs of urinary tract infection, genital mycotic infection, symptomatic hypoglycemia, and hypovolemia were low and not meaningfully different across groups.

Co-initiation of ertugliflozin with sitagliptin in patients with T2DM inadequately controlled on diet and exercise provided a clinically meaningful improvement in glycemic control over 26 weeks.

Clinicaltrials.gov NCT02226003.

To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes.

This was a 52-week, double-blind, multicentre, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (phase A), followed by a 26-week active-controlled treatment period (phase B) in 461 men and women, aged ≥18 years with inadequate glycaemic control (glycated haemoglobin [HbA1c] concentration 7.0% to 10.5% [53-91 mmol/mol], inclusive) despite diet and exercise. Results from phase A are reported in the present paper. The primary endpoint was the change in HbA1c from baseline to week 26.

At week 26, the placebo-adjusted least squares mean HbA1c changes from baseline were -0.99% and -1.16% for the ertugliflozin 5 and 15 mg doses, respectively ( P  < .001 for both doses). The odds of having HbA1c <7.0% (53 mmol/mol) were significantly greater in the ertugliflozin 5 and 15 mg groups compared with the placebo group. Both doses of ertugliflozin significantly lowered fasting plasma glucose and 2-hour postprandial glucose levels and body weight. The placebo-adjusted differences in changes from baseline in systolic blood pressure were not statistically significant. A higher incidence of genital mycotic infections occurred in men and women treated with ertugliflozin compared with placebo. There was no significant difference between treatments in the proportion of participants with symptomatic hypoglycaemia or adverse events associated with urinary tract infection or hypovolaemia.

Ertugliflozin 5 and 15 mg treatment for 26 weeks provides effective glycaemic control, reduces body weight and is generally well tolerated, when used as monotherapy.

Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has enabled remarkable reductions in cardiovascular and all-cause mortality as well as in renal outcomes in patients with type 2 diabetes (T2D) and a history of cardiovascular disease in the EMPA-REG OUTCOME. These results have been attributed to haemodynamic rather than metabolic effects, in part due to the osmotic/diuretic action of empagliflozin and the reduction in arterial blood pressure (BP). The present narrative review includes the results of meta-analyses of trials evaluating the effects on renal outcomes of lowering BP in patients with T2D, with a special focus on the influence of baseline and achieved systolic BP, and compares the renal outcome results of the EMPA-REG OUTCOME with those of other major trials with inhibitors of the renin-angiotensin system in patients with T2D and the preliminary findings with other SGLT2 inhibitors, and also evaluates post hoc analyses from the EMPA-REG OUTCOME of special interest as regards the BP-lowering hypothesis and renal function. While systemic BP reduction associated to empagliflozin therapy may have contributed to the renal benefits reported in EMPA-REG OUTCOME, other local mechanisms related to kidney homoeostasis most probably also played a role in the overall protection observed in the trial.

Currently available antihyperglycemic agents, despite being effective, provide inadequate glycemic control and/or are associated with side effects or nonadherence. Canagliflozin, a widely used orally active inhibitor of sodium-glucose cotransporter 2 (SGLT2), is a new addition to the therapeutic armamentarium of glucose-lowering drugs. This review summarizes findings from different clinical and observational studies of canagliflozin 300 mg in patients with type 2 diabetes mellitus (T2DM). By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose, thereby increasing urinary glucose excretion in patients with T2DM. Canagliflozin 300 mg has been shown to be effective in lowering glycated hemoglobin, fasting plasma glucose, and postprandial glucose in patients with T2DM. Canagliflozin 300 mg also demonstrated significant reductions in body weight and blood pressure and has a low risk of causing hypoglycemia, when not used in conjunction with insulin and insulin secretagogues. Canagliflozin 300 mg was generally well tolerated in clinical studies. The most frequently reported adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis, and volume depletion-related events.