The Effect of Sodium-Dependent Glucose Cotransporter 2 Inhibitor Tofogliflozin on Neurovascular Coupling in the Retina in Type 2 Diabetic Mice.

We investigated the effect of tofogliflozin, a sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i), on retinal blood flow dysregulation, neural retinal dysfunction, and the impaired neurovascular coupling in type 2 diabetic mice. Tofogliflozin was added to mouse chow to deliver 5 mg/kg/day and 6-week-old mice were fed for 8 weeks. The longitudinal changes in the retinal neuronal function and blood flow responses to systemic hyperoxia and flicker stimulation were evaluated every 2 weeks in diabetic db/db mice that received tofogliflozin (n =6) or placebo (n = 6) from 8 to 14 weeks of age. We also evaluated glial activation and vascular endothelial growth factor (VEGF) expression by immunofluorescence. Tofogliflozin treatment caused a sustained decrease in blood glucose in db/db mice from 8 weeks of the treatment. In tofogliflozin-treated db/db mice, both responses improved from 8 to 14 weeks of age, compared with vehicle-treated diabetic mice. Subsequently, the electroretinography implicit time for the oscillatory potential was significantly improved in SGLT2i-treated db/db mice. The systemic tofogliflozin treatment prevented the activation of glial fibrillary acidic protein and VEGF protein expression, as detected by immunofluorescence. Our results suggest that glycemic control with tofogliflozin significantly improved the impaired retinal neurovascular coupling in type 2 diabetic mice with the inhibition of retinal glial activation.

Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species.

SGLT-2i's exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i's empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i's (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i's improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i's might be partially mediated by inhibition of NHE1 and NOXs.

"The pharmacological profile of SGLT2 inhibitors: Focus on mechanistic aspects and pharmacogenomics".

Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-transporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with few side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response.

Sodium-glucose co-transporter inhibitors in insulin-treated diabetes: a meta-analysis.

BACKGROUND: Patients with insulin-treated type 2 diabetes (T2D) have a high risk of major adverse cardiovascular events. Sodium-glucose cotransporter inhibitors (SGLTi) improve outcomes without hypoglycaemic risk. AIMS: To study the effect of SGLTi in patients with T2D with and without background insulin treatment in outcome-driven RCTs. METHODS: Random effects models. RESULTS: A total of 54 374 patients with T2D were included in the analysis, of which 26 551 (48.8%) were treated with insulin. For 3P-MACE in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.93 (0.81-1.05), with moderate heterogeneity (I2 = 49.2%, Q statistic P = 0.11). In insulin-treated patients, the HR (95% CI) was 0.88 (0.82-0.95), without evidence of heterogeneity (I2 =0.0%, Q statistic P =0.91). The pooled effect evidenced a 10% reduction of 3P-MACE with SGLTi (HR: 0.90, 95% CI: 0.85-0.96), without SGLTi-by-insulin interaction P = 0.53. For the composite outcome of HF hospitalisation or cardiovascular death in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.77 (0.61-0.92), with marked heterogeneity (I2 = 66.8%, Q statistic P = 0.02). In insulin-treated patients, the HR (95% CI) was 0.77 (0.68-0.86), without significant heterogeneity (I2 = 31.7%, Q statistic P = 0.25). The pooled effect evidenced a 23% reduction of HF hospitalisations or cardiovascular death with SGLTi (HR: 0.77, 95% CI: 0.68-0.85), without SGLTi-by-insulin interaction P = 0.98. CONCLUSION: SGLTi reduces cardiovascular events regardless of insulin use. However, the treatment effect is more homogeneous among insulin-treated patients, supporting the use of SGLTi for the treatment of patients with T2D requiring insulin for glycaemic control.

Sodium/glucose cotransporter 2 inhibitors in chronic kidney disease and heart failure: ready for prime time in patients without diabetes.

PURPOSE OF REVIEW: The benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors seem to extend beyond glycemic control. We review recent randomized trial evidence evaluating SGLT2 inhibition in nondiabetic settings, including in patients with chronic kidney disease (CKD) and heart failure (HF). RECENT FINDINGS: DAPA-CKD, DAPA-HF and EMPEROR-Reduced compared SGLT2 inhibitors to placebo, enrolling 5868 patients without diabetes. In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) of 25-75 ml/min/1.73 m2 and macroalbuminuria irrespective of kidney disease aetiology had improved cardiovascular and kidney outcomes if randomized to receive SGLT2 inhibitors (primary composite endpoint: hazard ratio [HR] 0.61, 95% CI 0.51-0.72; absolute risk reduction [ARR] 5.3%). In DAPA-HF and EMPEROR-Reduced, participants with reduced ejection fraction (HFrEF) had improved cardiovascular outcomes when an SGLT2 inhibitor was added to guideline-directed medical therapy, mainly through a reduction in HF hospitalizations (HR 0.70, 95% CI 0.59-0.83; ARR 3.7% and HR 0.69, 95% CI 0.59-0.81; ARR 5.1% with dapagliflozin and empagliflozin, respectively). In all 3 trials, the benefits were not modified by diabetes, baseline eGFR or proteinuria. SUMMARY: SGLT2 inhibitors improve kidney and HF outcomes in patients with high-risk CKD and HFrEF, irrespective of diabetes. Clinicians should become more comfortable prescribing these medications as we await studies that may further broaden their indications.

Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices.

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit-risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit-risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit-Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit-risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.

Effects of Sodium-Glucose Cotransporter Inhibitor/Glucagon-Like Peptide-1 Receptor Agonist Add-On to Insulin Therapy on Glucose Homeostasis and Body Weight in Patients With Type 1 Diabetes: A Network Meta-Analysis.

Many patients with type 1 diabetes (T1D) do not achieve the glycemic target goal with insulin treatment. In this study, we aimed to evaluate the efficacy and safety of add-on to insulin therapy in patients with T1D. We conducted direct and indirect network meta-analyses using Bayesian models and ranked hypoglycemic agents via mixed treatment comparison, using data from the CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded databases. Randomized controlled trials (RCTs) involving patients with T1D treated with insulin and add-on metformin or sodium-glucose cotransporter inhibitors or glucagon-like peptide-1 receptor agonists from January 1970 to September 2019 were included in this study. Twenty-three RCTs with 5,151 subjects were divided into the following groups: insulin alone, insulin+metformin, insulin+canagliflozin, insulin+dapagliflozin, insulin+empagliflozin, insulin+sotagliflozin, insulin+liraglutide, and insulin+exenatide. HbA1c level in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group (mean difference: -0.43, 95% credible interval: -0.62 to -0.23). Total daily insulin dose in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group. Compared with that in the insulin alone group, body weight in the groups treated with insulin+add-on canagliflozin, sotagliflozin, and exenatide was significantly decreased by 4.5, 2.8, and 5.1 kg, respectively. Hypoglycemic episodes did not differ among the groups. In patients with T1D, insulin+sotagliflozin decreased the HbA1c level, daily insulin dose, and body weight without hypoglycemia compared with insulin monotherapy. Insulin+canagliflozin or insulin+exenatide was effective in reducing body weight compared with insulin alone. In conclusion, sotagliflozin treatment decreased not only the HbA1c levels and insulin dose but also the body weight without causing hypoglycemia in patients with T1D. Treatment with canagliflozin and exenatide effectively reduced body weight in patients with T1D. However, ketoacidosis associated with the use of SGLT inhibitors should be considered in these patients. Thus, our results suggest that sotagliflozin has a high probability of being ranked first as an adjunctive therapy to insulin in patients with T1D.

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application.

Sodium glucose transporters (SGLTs) belong to the mammalian solute carrier family SLC5. This family includes 12 different members in human that mediate the transport of sugars, vitamins, amino acids, or smaller organic ions such as choline. The SLC5 family belongs to the sodium symporter family (SSS), which encompasses transporters from all kingdoms of life. It furthermore shares similarity to the structural fold of the APC (amino acid-polyamine-organocation) transporter family. Three decades after the first molecular identification of the intestinal Na+-glucose cotransporter SGLT1 by expression cloning, many new discoveries have evolved, from mechanistic analysis to molecular genetics, structural biology, drug discovery, and clinical applications. All of these advances have greatly influenced physiology and medicine. While SGLT1 is essential for fast absorption of glucose and galactose in the intestine, the expression of SGLT2 is largely confined to the early part of the kidney proximal tubules, where it reabsorbs the bulk part of filtered glucose. SGLT2 has been successfully exploited by the pharmaceutical industry to develop effective new drugs for the treatment of diabetic patients. These SGLT2 inhibitors, termed gliflozins, also exhibit favorable nephroprotective effects and likely also cardioprotective effects. In addition, given the recent finding that SGLT2 is also expressed in tumors of pancreas and prostate and in glioblastoma, this opens the door to potential new therapeutic strategies for cancer treatment by specifically targeting SGLT2. Likewise, further discoveries related to the functional association of other SGLTs of the SLC5 family to human pathologies will open the door to potential new therapeutic strategies. We furthermore hope that the herein summarized information about the physiological roles of SGLTs and the therapeutic benefits of the gliflozins will be useful for our readers to better understand the molecular basis of the beneficial effects of these inhibitors, also in the context of the tubuloglomerular feedback (TGF), and the renin-angiotensin system (RAS). The detailed mechanisms underlying the clinical benefits of SGLT2 inhibition by gliflozins still warrant further investigation that may serve as a basis for future drug development.

[Relative frequency of urinary tract infections in patients affected by diabetes mellitus type 2 treated with metformin and SGLT2 inhibitor. Network meta-analysis]. / A húgyúti fertozések relatív gyakorisága metforminnal és SGLT2-gátlóval kezelt 2-es típusú diabetes mellitusban szenvedo betegekben. Hálózati metaanalízis.

Introduction and aim: The of this research was to conduct a network meta-analysis based on a systematic literature search to compare the relative frequency of urinary tract infections using sodium-glucose cotransporter-2 (SGLT2) inhibitors combined with metformin in the therapy of type 2 diabetes. Method: MEDLINE and EMBASE databases were searched to identify publications of randomized, controlled trials investigating SGLT2 inhibitors combined with metformin in the therapy of type 2 diabetes and providing information on the frequency of urinary tract infections. Results: 10 165 unique citations were screened to identify 10 publications to be included in the network meta-analysis. The network meta-analysis showed reduced risk of urinary tract infections for low-dose ertugliflozin compared to other SGLT2 inhibitors (ertugliflozin 5 mg vs. empagliflozin 10 mg: RR: 0.606, 95% CrI: 0.264-1.415; ertugliflozin 5 mg vs. dapagliflozin 10 mg: RR = 0.853, 95% CrI: 0.301-2.285). For high-dose comparisons, empagliflozin 25 mg showed reduced risk of urinary tract infections compared to both ertugliflozin 15 mg (RR = 0.745, 95% CrI 0.330-1.610) and dapagliflozin 10 mg (RR = 0.680, 95% CrI: 0.337-1.289). The difference between active substances and their doses was not statistically significant for the relative frequency of urinary tract infections. The meta-regression revealed a statistically significant association between baseline fasting plasma glucose level and relative frequency of urinary tract infections (ß = 0.785, 95% CrI: 0.062-1.587). Conclusion: There was no statistically significant difference between SGLT2 inhibitors investigated in this study in terms of the relative frequency of urinary tract infections. This research demonstrates the applicability of network meta-analyses when assessing the relative effectiveness and safety of interventions. Orv Hetil. 2020; 161(13): 491-501.

Inhibition of Sodium Glucose Cotransporters Improves Cardiac Performance.

The sodium-glucose cotransporter (SGLT) inhibitors represent a new alternative for treating patients with diabetes mellitus. They act primarily by inhibiting glucose reabsorption in the renal tubule and therefore, decreasing blood glucose levels. While little is yet known about SGLT subtype 1, SGLT2 inhibitors have demonstrated to significantly reduce cardiovascular mortality and heart failure hospitalizations. This cardioprotective benefit seems to be independent of their glucose-lowering properties; however, the underlying mechanism(s) remains still unclear and numerous hypotheses have been postulated to date. Moreover, preclinical research has suggested an important role of SGLT1 receptors on myocardial ischemia. Following acute phase of cardiac injury there is an increased activity of SGLT1 cotransport that ensures adequate energy supply to the cardiac cells. Nonetheless, a long-term upregulation of this receptor may not be that beneficial and whether its inhibition is positive or not should be further addressed. This review aims to present the most cutting-edge insights into SGLT receptors.

Molecular mechanism of vSGLT inhibition by gneyulin reveals antiseptic properties against multidrug-resistant gram-negative bacteria.

Faced with the worldwide spread of multidrug-resistant (MDR) bacterial strains, together with a lack of any appropriate treatment, urgent steps to combat infectious diseases should be taken. Usually, bacterial components are studied to understand, by analogy, the functioning of human proteins. However, molecular data from bacteria gathered over the past decades provide a sound basis for the search for novel approaches in medical care. With this current work, we want to direct attention to inhibition of the vSGLT glucose transporter from Vibrio parahaemolyticus belonging to the sodium solute symporter (SSS) family, to block sugar transport into the bacterial cell and, as a consequence, to limit its growth. Potential bacteriostatic properties can be drawn from commercially available drugs developed for human diseases. This goal can also be reached with natural components from traditional herbal medicine. The presented data from the numerical analysis of 44 known inhibitors of sodium glucose symporters shed light on potential novel approaches in fighting Gram-negative multidrug-resistant microorganisms. Graphical abstract Molecular view on vSGLT channel inhibition by gneyulin B, the compound of natural origin.

Sodium Glucose Co-transporter Inhibitors in Patients with Acromegaly and Diabetes.

Acromegaly per se predisposes to diabetes. Somatostatin analogs (SSAs) have an overall neutral effect on glycemic control. However, a marked increase in hyperglycemia was observed recently since the introduction of pasireotide long-acting release (PAS-LAR). Sodium glucose cotransporter inhibitors (SGLT2is) have proven their efficacy, cardiovascular safety, and superiority in the management of type 2 diabetes mellitus (T2DM). However, this class is rarely recommended for patients with diabetes and acromegaly. A decreased circulating insulin level is considered unique for this class and might have a beneficial role in the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis. Therefore, SGLT2is should be considered in the management of diabetes in patients with acromegaly. This article highlights the role of this novel class for the management of diabetes in patients with acromegaly.

The sodium-glucose co-transporter 2 inhibitor velagliflozin reduces hyperinsulinemia and prevents laminitis in insulin-dysregulated ponies.

There are no registered veterinary drugs for treating insulin dysregulation and preventing insulin-associated laminitis in horses. Velagliflozin is a sodium-glucose co-transport 2 inhibitor that reduces renal glucose reabsorption, promotes glucosuria, and consequently, decreases blood glucose and insulin concentrations. This study aimed to determine if velagliflozin reduced hyperinsulinemia and prevented laminitis in insulin-dysregulated ponies fed a challenge diet high in non-structural carbohydrates (NSC). An oral glucose test (1 g dextrose/kg BW) was used to screen 75 ponies for insulin dysregulation, of which 49 ponies with the highest insulin concentrations were selected. These animals were assigned randomly to either a treated group (n = 12) that received velagliflozin (0.3 mg/kg BW, p.o., s.i.d.) throughout the study, or a control group (n = 37). All ponies were fed a maintenance diet of alfalfa hay for 3 weeks, before transferring to a challenge diet (12 g NSC/kg BW/d) for up to 18 d. Blood glucose and serum insulin concentrations were measured over 4 h after feeding, on d 2 of the diet. The maximum glucose concentration was 22% lower (P = 0.014) in treated animals, with a geometric mean (95% CI) of 9.4 (8.0-11.0) mM, versus 12.1 (10.7-13.7) mM in the controls. This was reflected by lower (45%) maximum insulin concentrations in the treated group (P = 0.017), of 149 (97-228) µIU/mL, versus 272 (207-356) µIU/mL for controls. The diet induced Obel grade 1 or 2 laminitis in 14 of the 37 controls (38%), whereas no velagliflozin-treated pony developed laminitis (P = 0.011). Velagliflozin was well-tolerated, with no hypoglycemia or any clinical signs of adverse effects. The main limitation of this study was the sample size. Velagliflozin shows promise as a safe and effective compound for treating insulin dysregulation and preventing laminitis by reducing the hyperinsulinemic response to dietary NSC.

Sodium glucose cotransporters inhibitors in type 1 diabetes.

Sodium glucose cotransporter inhibitors (SGLTi) are oral hypoglycemic drugs that reduce renal glucose re-uptake and induce glycosuria. SGLTi have been successfully tested in large randomized clinical trials for type 2 diabetes, and several molecules have been approved in this setting by the international pharmaceutical agencies. Additionally, recent evidence has shown that SGLTi may be useful also in type 1 diabetes (T1D). Indeed, these drugs can be used as an ancillary to insulin to improve glycemic control and reduce insulin dosage, and such regimens have been associated with a lower rate of hypoglycemic episodes. The pharmacological effects of SGLTi therapy are described herein, and we also discuss the future use of SGLTi in T1D.

Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly alone, or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION-8 randomized controlled trial.

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

The Anticipated Renoprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors.

Sodium-glucose cotransporter 2 (SGLT2), which is specifically expressed on the apical side of proximal tubular cells, is involved in the reabsorption of most of the glucose filtered by the glomeruli, and its inhibitors are gaining publicity as potent antihyperglycemic drugs. In some clinical trials, SGLT2 inhibitors exerted cardiovascular and kidney protective effects, which appeared to be partly independent of the original glucose-lowering effect. SGLT2 inhibitors have both direct and indirect renoprotective effects. The direct effects involve the suppression of hyperplasia/hypertrophy, inflammation, and fibrosis in the proximal tubular cells, utilization of ketone bodies, restored tubuloglomerular feedback, decreased oxygen consumption, improvement in anemia, and preconditioning against ischemia/reperfusion. The indirect effects involve a reduction in insulin levels and resistance, uric acid concentration, body weight, and blood pressure. However, safety concerns remain, including consequences of an enhanced glucose load in the lower nephron, leg amputation, bone fractures, and therapeutic efficacy in patients with advanced chronic kidney disease.

[New antidiabetic drugs: current status and future prospects - a review of the literature].

425 million people worldwide suffer from diabetes. In patients with diabetes, insufficient glycemic control is associated with a high risk of developing micro- and macrovascular complications. The last decade has significantly contributed to extending the range of therapeutic options in the treatment of type 2 diabetes with new drugs that mimic ormodulate physiological processes in the human body. The paper summarizes the most important conclusions regarding the use of four groups of new drugs: thiazolidinediones, analogues of glucagon-like peptide 1, dipeptidyl peptidase-4 inhibitors and glucose-sodium 2 glucose cotransporter inhibitors, based on a review of the latest literature. These drugs have an anti-hyperglycemic effect and have numerous beneficial pleiotropic effects, including a safe cardiovascular profile. However, many of the mechanisms of action and effects of therapy, including side effects, new antidiabetic drugs remain unclear and require further clinical trials.

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes.

BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. METHODS: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. RESULTS: A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). CONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).